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1
Lu, X., J. J. Deadman, J. A. Williams, V. V. Kakkar, and S. Rahman. "Synthetic RGD peptides derived from the adhesive domains of snake-venom proteins: evaluation as inhibitors of platelet aggregation." Biochemical Journal 296, no. 1 (November 15, 1993): 21–24. http://dx.doi.org/10.1042/bj2960021.
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Synthetic peptides based on the RGD domains of the potent platelet aggregation inhibitors kistrin and dendroaspin were generated. The 13-amino-acid peptides were synthesized as dicysteinyl linear and disulphide cyclic forms. In platelet-aggregation studies, the cyclic peptides showed 3-fold better inhibition than their linear equivalents and approx. 100-fold greater potency than synthetic linear RGDS peptides derived from fibronectin. An amino acid substitution, Asp10→Ala, in the kistrin-based peptide gave a 4-fold decrease in potency in the linear peptide, but produced a 2-fold elevation in the inhibitory activity of the cyclic form, generating a peptide of potency comparable with that of the parent protein.
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Maroto, Alicia, Ricard Boqué, Dany Jeanne Dit Fouque, and Antony Memboeuf. "Energy-Resolved Mass Spectrometry and Mid-Infrared Spectroscopy for Purity Assessment of a Synthetic Peptide Cyclised by Intramolecular Huisgen Click Chemistry." Methods and Protocols 7, no. 6 (December 2, 2024): 97. https://doi.org/10.3390/mps7060097.
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Cyclic peptides have higher stability and better properties as therapeutic agents than their linear peptide analogues. Consequently, intramolecular click chemistry is becoming an increasingly popular method for the synthesis of cyclic peptides from their isomeric linear peptides. However, assessing the purity of these cyclic peptides by mass spectrometry is a significant challenge, as the linear and cyclic peptides have identical masses. In this paper, we have evaluated the analytical capabilities of energy-resolved mass spectrometry (ER MS) and mid-infrared microscopy (IR) to address this challenge. On the one hand, mixtures of both peptides were subjected to collision-induced dissociation tandem mass spectrometry (CID MS/MS) experiments in an ion trap mass spectrometer at several excitation energies. Two different calibration models were used: a univariate model (at a single excitation voltage) and a multivariate model (using multiple excitation voltages). The multivariate model demonstrated slightly enhanced analytical performance, which can be attributed to more effective signal averaging when multiple excitation voltages are considered. On the other hand, IR microscopy was used for the quantification of the relative amount of linear peptide. This was achieved through univariate calibration, based on the absorbance of an alkyne band specific to the linear peptide, and through Partial Least Squares (PLS) multivariate calibration. The PLS calibration model demonstrated superior performance in comparison to univariate calibration, indicating that consideration of the full IR spectrum is preferable to focusing on the specific peak of the linear peptide. The advantage of IR microscopy is that it is linear across the entire working interval, from linear peptide molar ratios of 0 (equivalent to pure cyclic peptide) up to 1 (pure linear peptide). In contrast, the ER MS calibration models exhibited linearity only up to 0.3 linear peptide molar ratio. However, ER MS showed better performances in terms of the limit of detection, intermediate precision and the root-mean-square-error of calibration. Therefore, ER MS is the optimal choice for the detection and quantification of the lowest relative amounts of linear peptides.
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Ulapane, Kopec, and Siahaan. "Improving In Vivo Brain Delivery of Monoclonal Antibody Using Novel Cyclic Peptides." Pharmaceutics 11, no. 11 (October 31, 2019): 568. http://dx.doi.org/10.3390/pharmaceutics11110568.
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Many proteins can be used to treat brain diseases; however, the presence of the blood–brain barrier (BBB) creates an obstacle to delivering them into the brain. Previously, various molecules were delivered through the paracellular pathway of the BBB via its modulation, using ADTC5 and HAV6 peptides. This study goal was to design new cyclic peptides with N-to-C terminal cyclization for better plasma stability and modulation of the BBB. Cyclic HAVN1 and HAVN2 peptides were derived from a linear HAV6 peptide. Linear and N-to-C terminal cyclic ADTHAV peptides were designed by combining the sequences of ADTC5 and HAV6. These novel cyclic peptides were used to deliver an IRdye800CW-labeled IgG monoclonal antibody into the brain. Cyclic HAVN1 and HAVN2 peptides deliver IgG into the brain, while the parent linear HAV6 peptide does not. Cyclic and linear ADTHAV and ADTC5 peptides enhanced brain delivery of IgG mAb, in which cyclic ADTHAV peptide was better than linear ADTHAV (p = 0.07). Cyclic ADTHAV and ADTC5 influenced the distribution of IgG mAb in other organs while HAV6, HAVN1 and HAVN2 did not. In summary, the novel cyclic peptides are generally better BBB modulators than their linear counterparts for delivering IgG mAb into the brain.
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Amirkhanov, N. V., A. V. Bardasheva, V. N. Silnikov, and N. V. Tikunova. "Synthetic Antimicrobial Peptides. V. Histidine-containing Antifungal Peptides with a “Linear” Type of Amphipathicity." Биоорганическая химия 50, no. 4 (October 25, 2024): 538–55. http://dx.doi.org/10.31857/s0132342324040135.
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A number of histidine-containing synthetic antifungal peptides with a “linear” type of amphipathicity (SAMP LTA) (F2Hx, H10F2, H10, where x = 7, 10, 13 and 16) have been synthesized and studied. Biological screening of such histidine-containing peptides for their antifungal and hemolytic activity was carried out. It has been shown that the presented histidine-containing SAMP LTAs are capable of effectively inhibiting the growth of opportunistic fungi Candida albicans and have low hemolytic activity in most cases not exceeding 10% even at their relatively high concentration of 400 μM in a medium containing erythrocytes. The antifungal activity of the studied peptides increases with increasing histidine residues in their composition, reaching the maximum value for the histidine-containing peptide F2H16 (MIC50 = 1.0 µM). It has been shown that as the chain length of peptides increases, their hemolytic toxicity also increases. In terms of therapeutic significance, the optimal peptides in the presented series of peptides were F2H10 and F2H13, which have higher selectivity than the short or longer peptides F2H7 or F2H16. The therapeutic index (TI) for these peptides was 233, 247, 79 and 60, respectively. It has been shown that histidine-containing derivatives of peptides with phenylalanine residues at the N-terminus of the peptide (F2H10) are less effective compared to similar peptides (H10F2) containing phenylalanine residues at the C-terminus. Among all the studied peptides, the most active was the H10 peptide (MIC50 = 0.7 µM), which does not contain phenylalanine residues, which in its antifungal activity is not only more effective than all other histidine-containing peptides, including the F2H16 peptide with 16 histidine residues, but also 4-5 times more effective than the antifungal peptide P113 (MIC50 = 3.4 µM), a short active fragment of natural histatin 5, well known in the literature. Due to its relatively low hemolytic and high antifungal activity, the presented histidine-containing SAMP LTAs have relatively high TI values, more than 60. Among all the studied peptides, peptides H10 and P113 have minimal, almost zero, hemolytic activity. However, due to its higher antifungal activity, the selectivity of peptide H10 (TI 1400) exceeds that of peptide P113 (TI 340) by more than 4 times. Thus, peptide H10, due to its high antifungal activity, low hemolytic toxicity and, accordingly, high therapeutic significance, can be used as a promising antifungal peptide drug.
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Bowen, John, John Schneible, Kaitlyn Bacon, Collin Labar, Stefano Menegatti, and Balaji M. Rao. "Screening of Yeast Display Libraries of Enzymatically Treated Peptides to Discover Macrocyclic Peptide Ligands." International Journal of Molecular Sciences 22, no. 4 (February 5, 2021): 1634. http://dx.doi.org/10.3390/ijms22041634.
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We present the construction and screening of yeast display libraries of post-translationally modified peptides wherein site-selective enzymatic treatment of linear peptides is achieved using bacterial transglutaminase. To this end, we developed two alternative routes, namely (i) yeast display of linear peptides followed by treatment with recombinant transglutaminase in solution; or (ii) intracellular co-expression of linear peptides and transglutaminase to achieve peptide modification in the endoplasmic reticulum prior to yeast surface display. The efficiency of peptide modification was evaluated via orthogonal detection of epitope tags integrated in the yeast-displayed peptides by flow cytometry, and via comparative cleavage of putative cyclic vs. linear peptides by tobacco etch virus (TEV) protease. Subsequently, yeast display libraries of transglutaminase-treated peptides were screened to isolate binders to the N-terminal region of the Yes-Associated Protein (YAP) and its WW domains using magnetic selection and fluorescence activated cell sorting (FACS). The identified peptide cyclo[E-LYLAYPAH-K] featured a KD of 1.75 μM for YAP and 0.68 μM for the WW domains of YAP as well as high binding selectivity against albumin and lysozyme. These results demonstrate the usefulness of enzyme-mediated cyclization in screening combinatorial libraries to identify cyclic peptide binders.
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Appel, J. R., C. Pinilla, H. Niman, and R. Houghten. "Elucidation of discontinuous linear determinants in peptides." Journal of Immunology 144, no. 3 (February 1, 1990): 976–83. http://dx.doi.org/10.4049/jimmunol.144.3.976.
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Abstract Synthetic peptides, made by the method of simultaneous multiple peptide synthesis, were coupled to the protein carrier keyhole limpet hemocyanin and used to raise mAb. Omission and substitution analogs of the original peptides were tested by ELISA to characterize their reactivity with the respective mAb. Linear antigenic determinants were located for 18 different peptides by using omission analogs. The length of the antigenic determinants ranged from 2 to 8 residues, with an average of 6 residues. The three aromatic amino acids, phenylalanine, tryptophan, and tyrosine, the charged hydrophilic amino acids, aspartic acid and lysine, and the neutral amino acid alanine were found to occur most often in the determinant region of the peptides tested, whereas asparagine, cysteine, and histidine occurred the least often. Alanine substitution analogs provided more information than omission analogs by enabling the determination of which side chain groups of the antigenic determinant residues were not critical for binding to the mAb. Detailed, "fingerprint" information about the interaction of the peptide, GASPYPNLSNQQT, and its mAb was obtained by synthesizing a complete series of analogs with individual substitutions for each position of the antigenic determinant, PYPNLS, with the 19 other amino acids. These results suggest that, at the amino acid level, all antigenic determinants of synthetic peptides defined by mAb can be considered discontinuous linear determinants.
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Kelil, Abdellali, Emmanuel D. Levy, and Stephen W. Michnick. "Evolution of domain–peptide interactions to coadapt specificity and affinity to functional diversity." Proceedings of the National Academy of Sciences 113, no. 27 (June 17, 2016): E3862—E3871. http://dx.doi.org/10.1073/pnas.1518469113.
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Evolution of complexity in eukaryotic proteomes has arisen, in part, through emergence of modular independently folded domains mediating protein interactions via binding to short linear peptides in proteins. Over 30 years, structural properties and sequence preferences of these peptides have been extensively characterized. Less successful, however, were efforts to establish relationships between physicochemical properties and functions of domain–peptide interactions. To our knowledge, we have devised the first strategy to exhaustively explore the binding specificity of protein domain–peptide interactions. We applied the strategy to SH3 domains to determine the properties of their binding peptides starting from various experimental data. The strategy identified the majority (∼70%) of experimentally determined SH3 binding sites. We discovered mutual relationships among binding specificity, binding affinity, and structural properties and evolution of linear peptides. Remarkably, we found that these properties are also related to functional diversity, defined by depth of proteins within hierarchies of gene ontologies. Our results revealed that linear peptides evolved to coadapt specificity and affinity to functional diversity of domain–peptide interactions. Thus, domain–peptide interactions follow human-constructed gene ontologies, which suggest that our understanding of biological process hierarchies reflect the way chemical and thermodynamic properties of linear peptides and their interaction networks, in general, have evolved.
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Panayi, Tolis, Spiridoula Diavoli, Vicky Nicolaidou, Christos Papaneophytou, Christos Petrou, and Yiannis Sarigiannis. "Short-Chained Linear Scorpion Peptides: A Pool for Novel Antimicrobials." Antibiotics 13, no. 5 (May 5, 2024): 422. http://dx.doi.org/10.3390/antibiotics13050422.
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Scorpion venom peptides are generally classified into two main groups: the disulfide bridged peptides (DBPs), which usually target membrane-associated ion channels, and the non-disulfide bridged peptides (NDBPs), a smaller group with multifunctional properties. In the past decade, these peptides have gained interest because most of them display functions that include antimicrobial, anticancer, haemolytic, and anti-inflammatory activities. Our current study focuses on the short (9–19 amino acids) antimicrobial linear scorpion peptides. Most of these peptides display a net positive charge of 1 or 2, an isoelectric point at pH 9–10, a broad range of hydrophobicity, and a Grand Average of Hydropathy (GRAVY) Value ranging between −0.05 and 1.7. These features allow these peptides to be attracted toward the negatively charged phospholipid head groups of the lipid membranes of target cells, a force driven by electrostatic interactions. This review outlines the antimicrobial potential of short-chained linear scorpion venom peptides. Additionally, short linear scorpion peptides are in general more attractive for large-scale synthesis from a manufacturing point of view. The structural and functional diversity of these peptides represents a good starting point for the development of new peptide-based therapeutics.
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New, Roger R. C., Tam T. T. Bui, and Michal Bogus. "Binding Interactions of Peptide Aptamers." Molecules 25, no. 24 (December 21, 2020): 6055. http://dx.doi.org/10.3390/molecules25246055.
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Peptide aptamers are short amino acid chains that are capable of binding specifically to ligands in the same way as their much larger counterparts, antibodies. Ligands of therapeutic interest that can be targeted are other peptide chains or loops located on the surface of protein receptors (e.g., GCPR), which take part in cell-to-cell communications either directly or via the intermediary of hormones or signalling molecules. To confer on aptamers the same sort of conformational rigidity that characterises an antibody binding site, aptamers are often constructed in the form of cyclic peptides, on the assumption that this will encourage stronger binding interactions than would occur if the aptamers were simply linear chains. However, no formal studies have been conducted to confirm the hypothesis that linear peptides will engage in stronger binding interactions with cyclic peptides than with other linear peptides. In this study, the interaction of a model cyclic decamer with a series of linear peptide constructs was compared with that of a linear peptide with the same sequence, showing that the cyclic configuration does confer benefits by increasing the strength of binding.
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Pullen, Jeffrey K., George W. Anderson, Susan L. Welkos, and Arthur M. Friedlander. "Analysis of the Yersinia pestis V Protein for the Presence of Linear Antibody Epitopes." Infection and Immunity 66, no. 2 (February 1, 1998): 521–27. http://dx.doi.org/10.1128/iai.66.2.521-527.1998.
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ABSTRACT The V protein expressed by pathogenic Yersinia pestisis an important virulence factor and protective immunogen. The presence of linear B-cell epitopes in the V protein was investigated by using a series of 17 overlapping linear peptides. Groups of 10 mice were immunized intraperitoneally with 30 μg of each peptide on days 0, 30, and 60. Although the V protein-specific antibody response to the peptides varied, most of the peptides elicited high antibody titers. The immunized mice were challenged subcutaneously with 60 50% lethal doses (LD50) (1 LD50 = 1.9 CFU) of a virulent Y. pestis strain, CO92. None of the peptide-immunized mice survived challenge. The animals immunized with the V protein were completely protected against challenge. The immunogenicity of some of the V peptides was increased by conjugating them to keyhole limpet hemocyanin. Only one peptide (encompassing amino acids 1 to 30) conjugate demonstrated some protection; the others were not protective. In additional experiments, V peptides that reacted well with sera from mice surviving Y. pestis infection were combined and used to immunize mice. Although the combined peptides appeared to be very immunogenic, they were not protective. Therefore, the protective B-lymphocyte epitope(s) in the V protein is most likely to be conformational.
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Zhang, Dingwa, Deyong He, Xiaoliang Pan, and Lijun Liu. "Rational Design and Intramolecular Cyclization of Hotspot Peptide Segments at YAP–TEAD4 Complex Interface." Protein & Peptide Letters 27, no. 10 (November 2, 2020): 999–1006. http://dx.doi.org/10.2174/0929866527666200414160723.
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Background: The Yes-Associated Protein (YAP) is a central regulator of Hippo pathway involved in carcinogenesis, which functions through interaction with TEA Domain (TEAD) transcription factors. Pharmacological disruption of YAP–TEAD4 complexes has been recognized as a potential therapeutic strategy against diverse cancers by suppressing the oncogenic activity of YAP. Objective: Two peptides, termed PS-1 and PS-2 are split from the interfacial context of YAP protein. Dynamics simulations, energetics analyses and fluorescence polarizations are employed to characterize the intrinsic disorder as well as binding energy/affinity of the two YAP peptides to TEAD4 protein. Methods: Two peptides, termed PS-1 and PS-2 are split from the interfacial context of YAP protein. Dynamics simulations, energetics analyses and fluorescence polarizations are employed to characterize the intrinsic disorder as well as binding energy/affinity of the two YAP peptides to TEAD4 protein. Result: The native conformation of PS-2 peptide is a cyclic loop, which is supposed to be constrained by adding a disulfide bond across the spatially vicinal residue pair Arg87-Phe96 or Met86- Phe95 at the peptide’s two ends, consequently resulting in two intramolecular cyclized counterparts of linear PS-2 peptide, namely PS-2(cyc87,96) and PS-2(cyc86,95). The linear PS-2 peptide is determined as a weak binder of TEAD4 (Kd = 190 μM), while the two cyclic PS-2(cyc87,96) and PS-2(cyc86,95) peptides are measured to have moderate or high affinity towards TEAD4 (Kd = 21 and 45 μM, respectively). Conclusion: PS-1 and PS-2 peptides are highly flexible and cannot maintain in native active conformation when splitting from the interfacial context, and thus would incur a considerable entropy penalty upon rebinding to the interface. Cyclization does not influence the direct interaction between PS-2 peptide and TEAD4 protein, but can largely reduce the intrinsic disorder of PS-2 peptide in free state and considerably minimize indirect entropy effect upon the peptide binding.
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GOEDHALS, D., J. T. PAWESKA, and F. J. BURT. "Identification of human linear B-cell epitope sites on the envelope glycoproteins of Crimean-Congo haemorrhagic fever virus." Epidemiology and Infection 143, no. 7 (September 4, 2014): 1451–56. http://dx.doi.org/10.1017/s0950268814002271.
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SUMMARYA peptide library was used to screen for regions containing potential linear B-cell epitope sites in the glycoproteins and nucleoprotein of Crimean-Congo haemorrhagic fever virus (CCHFV) in an enzyme-linked immunosorbent assay (ELISA). The library consisted of 156 peptides, spanning the nucleoprotein and mature GN and GC proteins in a 19-mer with 9-mer overlap format. Using pooled serum samples from convalescent patients to screen the library, six peptides were identified as potential epitope sites. Further testing of these six peptides with individual patient sera identified two of these peptides as probable epitope sites, with peptide G1451–1469 reacting to 13/15 and peptide G1613–1631 to 14/15 human sera. These peptides are situated on the GC protein at amino acid positions 1451–1469 (relative to CCHFV isolate SPU103/97) (TCTGCYACSSGISCKVRIH) and 1613–1631 (FMFGWRILFCFKCCRRTRG). Identified peptides may have application in ELISA for diagnostic or serosurveillance purposes.
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Rogers, Joseph M., Toby Passioura, and Hiroaki Suga. "Nonproteinogenic deep mutational scanning of linear and cyclic peptides." Proceedings of the National Academy of Sciences 115, no. 43 (October 9, 2018): 10959–64. http://dx.doi.org/10.1073/pnas.1809901115.
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High-resolution structure–activity analysis of polypeptides requires amino acid structures that are not present in the universal genetic code. Examination of peptide and protein interactions with this resolution has been limited by the need to individually synthesize and test peptides containing nonproteinogenic amino acids. We describe a method to scan entire peptide sequences with multiple nonproteinogenic amino acids and, in parallel, determine the thermodynamics of binding to a partner protein. By coupling genetic code reprogramming to deep mutational scanning, any number of amino acids can be exhaustively substituted into peptides, and single experiments can return all free energy changes of binding. We validate this approach by scanning two model protein-binding peptides with 21 diverse nonproteinogenic amino acids. Dense structure–activity maps were produced at the resolution of single aliphatic atom insertions and deletions. This permits rapid interrogation of interaction interfaces, as well as optimization of affinity, fine-tuning of physical properties, and systematic assessment of nonproteinogenic amino acids in binding and folding.
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Paterson, David J., Manlio Tassieri, Julien Reboud, Rab Wilson, and Jonathan M. Cooper. "Lipid topology and electrostatic interactions underpin lytic activity of linear cationic antimicrobial peptides in membranes." Proceedings of the National Academy of Sciences 114, no. 40 (September 20, 2017): E8324—E8332. http://dx.doi.org/10.1073/pnas.1704489114.
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Linear cationic antimicrobial peptides are a diverse class of molecules that interact with a wide range of cell membranes. Many of these peptides disrupt cell integrity by forming membrane-spanning pores that ultimately lead to their death. Despite these peptides high potency and ability to evade acquired bacterial drug resistance, there is a lack of knowledge on their selectivity and activity mechanisms. Such an understanding would provide an informative framework for rational design and could lead to potential antimicrobial therapeutic targets. In this paper, we use a high-throughput microfluidic platform as a quantitative screen to assess peptide activity and selectivity by precisely controlling exposure to vesicles with lipid compositions that mimic both bacterial and mammalian cell membranes. We explore the complexity of the lipid–peptide interactions governing membrane-disruptive behaviors and establish a link between peptide pore formation and both lipid–peptide charge and topological interactions. We propose a topological model for linear antimicrobial peptide activity based on the increase in membrane strain caused by the continuous adsorption of peptides to the target vesicle coupled with the effects of both lipid–peptide charge and topographical interactions. We also show the validity of the proposed model by investigating the activity of two prototypical linear cationic peptides: magainin 2 amide (which is selective for bacterial cells) and melittin (which targets both mammalian and bacterial cells indiscriminately). Finally, we propose the existence of a negative feedback mechanism that governs the pore formation process and controls the membrane’s apparent permeability.
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Rybina, A. V., V. S. Skvortsov, A. T. Kopylov, and V. G. Zgoda. "A plain method of prediction of visibility of peptides in mass spectrometry with electrospray ionization." Biomeditsinskaya Khimiya 60, no. 6 (2014): 707–12. http://dx.doi.org/10.18097/pbmc20146006707.
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A new method for screening of essential peptides for protein detection and quantification analysis in the direct positive electrospray mass spectrometry has been proposed. Our method is based on the prediction of the normalized abundance of the mass spectrometric peaks using a linear regression model. This method has the folowing limitations: (i) selected peptides should be taken so that at pH 2.5 the tested peptides must be presented mainly as the 2+ and 3+ ions; (ii) only peptides having C-terminal lysine or arginine residues are considered. The amino acid composition of the peptide, the peptide concentration, the ratio of the polar surface of peptide to common surface and ratio of the polar volume to common volume are used as independent variables in equation. Several combinations of variables were considered and the best linear regression model had a determination coefficient in leave-one-out validation procedure equal 0.54. This model confidently discriminates peptides with high response ability and peptides with low response ability, and therefore it allows to select only the most promising peptides. This screening method, a plain and fast, can be successfully applied to reduce the list of observed peptides.
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Schmidt, M. A., P. O'Hanley, and G. K. Schoolnik. "Gal-Gal pyelonephritis Escherichia coli pili linear immunogenic and antigenic epitopes." Journal of Experimental Medicine 161, no. 4 (April 1, 1985): 705–17. http://dx.doi.org/10.1084/jem.161.4.705.
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The linear immunogenic and antigenic structure of E. coli Gal-Gal pili from the recombinant strain HU 849 was investigated with nine synthetic peptides corresponding to regions of the pilus sequence predicted to contain hydrophilic beta-turns. Five peptides, as bovine serum albumin conjugates, were found by anti-HU 849 pilus serum and were thus designated "immunogenic epitopes." Peptides corresponding to R 25-38, R 38-50, and R 48-61 (which jointly comprise the single intramolecular disulfide loop), and R 103-116, were bound in low titer. A prominent immunogenic epitope was specified by a peptide corresponding to R 65-75. Four peptides, as thyroglobulin conjugates, elicited antisera in rabbits that bound intact HU 849 pili. These were designated "antigenic epitopes." Two prominent antigenic epitopes were localized to peptides corresponding to R 5-12 and R 93-104, whereas peptides corresponding to R 65-75 and R 119-131 represented two minor antigenic epitopes. None of the peptide antisera bound Gal-Gal pili from heterologous strains except anti-R 93-104 and anti-R 5-12. In 8 of the 10 Gal-Gal-binding pyelonephritis isolates tested, anti-R 5-12 detected a protein with an apparent molecular weight of 18,000 co-migrating with several Gal-Gal pili. Anti-R 93-104 detected a corresponding protein in 4 of 8 fecal and 7 of 12 pyelonephritis Gal-Gal-binding isolates; however, it also bound apparently unrelated proteins of higher molecular weight.
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Megaly, Alhussin Mohamed Abdelhakeem, Masahiro Miyashita, Mohammed Abdel-Wahab, Yoshiaki Nakagawa, and Hisashi Miyagawa. "Molecular Diversity of Linear Peptides Revealed by Transcriptomic Analysis of the Venom Gland of the Spider Lycosa poonaensis." Toxins 14, no. 12 (December 3, 2022): 854. http://dx.doi.org/10.3390/toxins14120854.
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Spider venom is a complex mixture of bioactive components. Previously, we identified two linear peptides in Lycosa poonaensis venom using mass spectrometric analysis and predicted the presence of more linear peptides therein. In this study, a transcriptomic analysis of the L. poonaensis venom gland was conducted to identify other undetermined linear peptides in the venom. The results identified 87 contigs encoding peptides and proteins in the venom that were similar to those in other spider venoms. The number of contigs identified as neurotoxins was the highest, and 15 contigs encoding 17 linear peptide sequences were identified. Seven peptides that were representative of each family were chemically synthesized, and their biological activities were evaluated. All peptides showed significant antibacterial activity against Gram-positive and Gram-negative bacteria, although their selectivity for bacterial species differed. All peptides also exhibited paralytic activity against crickets, but none showed hemolytic activity. The secondary structure analysis based on the circular dichroism spectroscopy showed that all these peptides adopt an amphiphilic α-helical structure. Their activities appear to depend on the net charge, the arrangement of basic and acidic residues, and the hydrophobicity of the peptides.
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Ma, Menglin, Jihong Li, and Bruce A. McClane. "Structure-Function Analysis of Peptide Signaling in the Clostridium perfringens Agr-Like Quorum Sensing System." Journal of Bacteriology 197, no. 10 (March 16, 2015): 1807–18. http://dx.doi.org/10.1128/jb.02614-14.
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ABSTRACTThe accessory growth regulator (Agr)-like quorum sensing (QS) system ofClostridium perfringenscontrols the production of many toxins, including beta toxin (CPB). We previously showed (J. E. Vidal, M. Ma, J. Saputo, J. Garcia, F. A. Uzal, and B. A. McClane, Mol Microbiol 83:179–194, 2012,http://dx.doi.org/10.1111/j.1365-2958.2011.07925.x) that an 8-amino-acid, AgrD-derived peptide named 8-R upregulates CPB production by this QS system. The current study synthesized a series of small signaling peptides corresponding to sequences within theC. perfringensAgrD polypeptide to investigate theC. perfringensautoinducing peptide (AIP) structure-function relationship. When both linear and cyclic ring forms of these peptides were added toagrBnull mutants of type B strain CN1795 or type C strain CN3685, the 5-amino-acid peptides, whether in a linear or ring (thiolactone or lactone) form, induced better signaling (more CPB production) than peptide 8-R for bothC. perfringensstrains. The 5-mer thiolactone ring peptide induced faster signaling than the 5-mer linear peptide. Strain-related variations in sensing these peptides were detected, with CN3685 sensing the synthetic peptides more strongly than CN1795. Consistent with those synthetic peptide results, Transwell coculture experiments showed that CN3685 exquisitely senses native AIP signals from other isolates (types A, B, C, and D), while CN1795 barely senses even its own AIP. Finally, aC. perfringensAgrD sequence-based peptide with a 6-amino-acid thiolactone ring interfered with CPB production by severalC. perfringensstrains, suggesting potential therapeutic applications. These results indicate that AIP signaling sensitivity and responsiveness vary amongC. perfringensstrains and suggestC. perfringensprefers a 5-mer AIP to initiate Agr signaling.IMPORTANCEClostridium perfringenspossesses an Agr-like quorum sensing (QS) system that regulates virulence, sporulation, and toxin production. The current study used synthetic peptides to identify the structure-function relationship for the signaling peptide that activates this QS system. We found that a 5-mer peptide induces optimal signaling. Unlike other Agr systems, a linear version of this peptide (in addition to thiolactone and lactone versions) could induce signaling. TwoC. perfringensstrains were found to vary in sensitivity to these peptides. We also found that a 6-mer peptide can inhibit toxin production by some strains, suggesting therapeutic applications.
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Pashova-Dimova, Shina, Peter Petrov, Sena Karachanak-Yankova, and Anastas Pashov. "Neurodegenerative diseases associated antibody repertoire signatures in mimotope arrays based on cyclic versus linear peptides." Pharmacia 70, no. 4 (November 30, 2023): 1439–47. http://dx.doi.org/10.3897/pharmacia.70.e115179.
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The role of peptide probes’ conformational flexibility in extracting immunosignatures has not been sufficiently studied. Immunosignatures profile the antibody diversity and prove promising for early cancer detection and multi-disease diagnostics. A novel tool for modeling antibody repertoires, the concept of antibody reactivity graphs, proved instrumental in this respect. Serum samples from patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia of unknown etiology (DUE), and healthy controls were probed using a set of 130 7-mer peptides relevant to neurodegenerative diseases. Results show that linear peptides probed with IgM yielded higher graph density compared to IgG, indicating different levels of polyspecificities. Additionally, the impact of peptide topology and antibody isotype on feature selection was studied using recursive feature elimination. Findings reveal that IgM assays on linear peptides offer superior diagnostic differentiation of neurodegenerative diseases and define the degree of agreement between IgG and IgM immunosignatures with linear or cyclic peptides.
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Northfield, Susan E., Simon J. Mountford, Jerome Wielens, Mengjie Liu, Lei Zhang, Herbert Herzog, Nicholas D. Holliday, et al. "Propargyloxyproline Regio- and Stereoisomers for Click-Conjugation of Peptides: Synthesis and Application in Linear and Cyclic Peptides." Australian Journal of Chemistry 68, no. 9 (2015): 1365. http://dx.doi.org/10.1071/ch15146.
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The use of the click reaction for the introduction of conjugate groups, such as affinity or fluorescent labels, to a peptide for the study of peptide biochemistry and pharmacology is widespread. However, the nature and location of substituted 1,2,3-triazoles in peptide sequences may markedly affect conformation or binding as compared with native sequences. We have examined the preparation and application of propargyloxyproline (Pop) residues as a precursor to such peptide conjugates. Pop residues are available in a range of regio- and stereoisomers from hydroxyproline precursors and are readily prepared in Fmoc-protected form. They can be incorporated routinely in peptide synthesis and broadly retain the conformational properties of the parent proline containing peptides. This is exemplified by the preparation of biotin- and fluorophore-labelled peptides derived from linear and cyclic peptides.
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Deschamps, J. R., C. George, C. Moore, R. Cudney, and J. L. Flippen-Anderson. "Constrained linear opioid peptides." Acta Crystallographica Section A Foundations of Crystallography 52, a1 (August 8, 1996): C249. http://dx.doi.org/10.1107/s0108767396089489.
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Gudivada, Vijaya Narasimha, Chen-Ji Huang, Yueh-Hsia Luo, and Guo-Chung Dong. "A Cyclic BMP-2 Peptide Upregulates BMP-2 Protein-Induced Cell Signaling in Myogenic Cells." Polymers 13, no. 15 (July 31, 2021): 2549. http://dx.doi.org/10.3390/polym13152549.
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In the current study, we designed four cyclic peptide analogues by incorporating two cysteine residues in a BMP-2 linear knuckle epitope in such a way that the active region of the peptide could be either inside or outside the cyclic ring. Bone morphogenetic protein receptor BMPRII was immobilized on the chip surface, and the interaction of the linear and cyclic peptide analogues was studied using surface plasmon resonance (SPR). From the affinity data, the peptides with an active region inside the cyclic ring had a higher binding affinity in comparison to the other peptides. To confirm that our affinity data are in line in vitro, we studied the expression levels of RUNX2 (runt-related transcription factor) and conducted an osteogenic marker alkaline phosphatase (ALP) assay and staining. Based on the affinity data and the in vitro experiments, peptide P-05 could be a suitable candidate for osteogenesis, with higher binding affinity and increased RUNX2 and ALP expression in comparison to the linear peptides.
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Solarte, Víctor A., Jaiver E. Rosas, Zuly J. Rivera, Martha L. Arango-Rodríguez, Javier E. García, and Jean-Paul Vernot. "A Tetrameric Peptide Derived from Bovine Lactoferricin Exhibits Specific Cytotoxic Effects against Oral Squamous-Cell Carcinoma Cell Lines." BioMed Research International 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/630179.
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Several short linear peptides derived from cyclic bovine lactoferricin were synthesized and tested for their cytotoxic effect against the oral cavity squamous-cell carcinoma (OSCC) cell lines CAL27 and SCC15. As a control, an immortalized and nontumorigenic cell line, Het-1A, was used. Linear peptides based on the RRWQWR core sequence showed a moderate cytotoxic effect and specificity towards tumorigenic cells. A tetrameric peptide, LfcinB(20–25)4, containing the RRWQWR motif, exhibited greater cytotoxic activity (>90%) in both OSCC cell lines compared to the linear lactoferricin peptide or the lactoferrin protein. Additionally, this tetrameric peptide showed the highest specificity towards tumorigenic cells among the tested peptides. Interestingly, this effect was very fast, with cell shrinkage, severe damage to cell membrane permeability, and lysis within one hour of treatment. Our results are consistent with a necrotic effect rather than an apoptotic one and suggest that this tetrameric peptide could be considered as a new candidate for the therapeutic treatment of OSCC.
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Wu, Zhenyu, Xiaoli Hou, and Hongbo Zhang. "Abstract 4463: A novel method for constructing diverse cyclic peptide libraries for efficient screening of PPI inhibitors." Cancer Research 85, no. 8_Supplement_1 (April 21, 2025): 4463. https://doi.org/10.1158/1538-7445.am2025-4463.
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Abstract Cyclic peptides drug design and discovery has experienced a resurgence of interest due to their target specificity and metabolic stability. In this study, we developed a novel methodology for generating extensive, structurally diverse, and synthesizable virtual libraries of cyclic peptides. Such libraries are essential for the identification of hit compounds against a spectrum of therapeutic targets through screening assays. We introduce an innovative strategy for the creation of diverse cyclic peptide libraries leveraging a “hierarchical generation” approach combined with artificial intelligence (AI)-driven sampling. Our approach begins with the generation of a library of representative linear peptides which are subsequently subjected to cyclization via an array of cyclization reactions. The generation of linear peptides is executed via a hierarchical generation method wherein amino acids are initially categorized according to their physicochemical properties. Next, a sequence of these properties is formulated, and the similarity of these property sequences is calculated through sequence alignment algorithm. Low-similarity property sequences are then processed by AI models to generated multiple sequences of amino acids, while high-similarity sequences are judiciously excluded. The iteration of this process yields a set of representative linear peptides, which are then cyclized to produce the desired cyclic peptides. Employing this novel methodology, we have successfully generated a virtual cyclic peptide library encompassing nearly 6 million molecular cyclic peptides (covering approximately 4 thousand trillion peptides) within a single week. Over 1000 representative cyclic peptides were selected for synthesis via the solid-phase peptide synthesis (SPPS) technique, and a cyclic peptide library with high structural diversity was obtained. In conclusion, the structural diversity of our library, combined with the successful screening results, highlights the robustness of our method in designing diverse cyclic peptides, particularly for hit identification against traditionally undruggable targets. Our findings underscore the utility of this cyclic peptide library in discovering potential PPI inhibitors. Citation Format: Zhenyu Wu, Xiaoli Hou, Hongbo Zhang. A novel method for constructing diverse cyclic peptide libraries for efficient screening of PPI inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4463.
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Jin, Yi, Janet Hammer, Michelle Pate, Yu Zhang, Fang Zhu, Erik Zmuda, and Jack Blazyk. "Antimicrobial Activities and Structures of Two Linear Cationic Peptide Families with Various Amphipathic β-Sheet and α-Helical Potentials." Antimicrobial Agents and Chemotherapy 49, no. 12 (December 2005): 4957–64. http://dx.doi.org/10.1128/aac.49.12.4957-4964.2005.
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ABSTRACT Many naturally occurring antimicrobial peptides comprise cationic linear sequences with the potential to adopt an amphipathic α-helical conformation. We designed a linear 18-residue peptide that adopted an amphipathic β-sheet structure when it was bound to lipids. In comparison to a 21-residue amphipathic α-helical peptide of equal charge and hydrophobicity, this peptide possessed more similar antimicrobial activity and greater selectivity in binding to and inducing leakage in vesicles composed of bacterial membrane lipids than vesicles composed of mammalian membrane lipids (J. Blazyk, R. Weigand, J. Klein, J. Hammer, R. M. Epand, R. F. Epand, W. L. Maloy, and U. P. Kari, J. Biol. Chem. 276:27899-27906, 2001). Here, we compare two systematically designed families of linear cationic peptides to evaluate the importance of amphipathicity for determination of antimicrobial activity. Each peptide contains six lysine residues and is amidated at the carboxyl terminus. The first family consists of five peptides with various capacities to form amphipathic β-sheet structures. The second family consists of six peptides with various potentials to form amphipathic α helices. Only those peptides that can form a highly amphipathic structure (either a β sheet or an α helix) possessed significant antimicrobial activities. Striking differences in the abilities to bind to and induce leakage in membranes and lipid vesicles were observed for the two families. Overall, the amphipathic β-sheet peptides are less lytic than their amphipathic α-helical counterparts, particularly toward membranes containing phosphatidylcholine, a lipid commonly found in mammalian plasma membranes. Thus, it appears that antimicrobial peptides that can form an amphipathic β-sheet conformation may offer a selective advantage in targeting bacterial cells.
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Wądrzyk, Magdalena, Julia Miśkiewicz, and Paulina Kasperkiewicz-Wasilewska. "PEPTYDOWE ZWIĄZKI MAKROCYKLICZNE: NOWE PERSPEKTYWY W DIAGNOSTYCE I TERAPII CHORÓB." Wiadomości Chemiczne 78, no. 11 (December 5, 2024): 1405–45. https://doi.org/10.53584/wiadchem.2024.11.1.
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PEPTYDOWE ZWIĄZKI MAKROCYKLICZNE 1407 ABSTRACT In recent years macrocyclic peptides have drawn much interest due to their beneficial physiochemical properties and potential medical applications. The goal of this review is to summarize the advantages and drawbacks of macrocyclic peptides and provide examples of their use as therapeutic agents. Macrocyclic peptides are characterized by better stability, selectivity and resistance to degradation than their linear counterparts, but on the other hand, macrocyclic peptide synthesis has low efficiency due to possible side reactions and difficulties with solubility of linear precursors. Macrocyclic peptides might also be more immunogenic than their linear counterparts. Macrocyclic peptides have been found as an promising group of molecules for innovative medicine and, to date, they are used as antimicrobial drugs which are effective against both bacteria and fungi. As macrocyclic peptides are highly selective, they also serve a role in cancer therapies and diagnostics. Patented macrocyclic peptides act as a scaffold for the search and optimization of specific inhibitors of cell signaling pathways used by cancer cells to avoid cell death. The presence of peptide rings in the structure of macrocyclic peptides makes them analogs of hormones, such as somatostatin and insulin. As a result, macrocyclic peptides could prove to be a good basis for the development of hormonal drugs with extended duration of action. Aside from their role in medicine macrocyclic peptides might also be used in the field of chemical biology as selective and specific chemical probes which would allow for the visualization and imagining of various molecular targets
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Vengesai, Arthur, Marble Manuwa, Herald Midzi, Masimba Mandeya, Victor Muleya, Keith Mujeni, Isaac Chipako, and Takafira Mduluza. "Identification of Schistosoma haematobium and Schistosoma mansoni linear B-cell epitopes with diagnostic potential using in silico immunoinformatic tools and peptide microarray technology." PLOS Neglected Tropical Diseases 18, no. 8 (August 22, 2024): e0011887. http://dx.doi.org/10.1371/journal.pntd.0011887.
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Introduction Immunoinformatic tools can be used to predict schistosome-specific B-cell epitopes with little sequence identity to human proteins and antigens other than the target. This study reports an approach for identifying schistosome peptides mimicking linear B-cell epitopes using in-silico tools and peptide microarray immunoassay validation. Method Firstly, a comprehensive literature search was conducted to obtain published schistosome-specific peptides and recombinant proteins with the best overall diagnostic performances. For novel peptides, linear B-cell epitopes were predicted from target recombinant proteins using ABCpred, Bcepred and BepiPred 2.0 in-silico tools. Together with the published peptides, predicted peptides with the highest probability of being B-cell epitopes and the lowest sequence identity with proteins from human and other pathogens were selected. Antibodies against the peptides were measured in sera, using peptide microarray immunoassays. Area under the ROC curve was calculated to assess the overall diagnostic performances of the peptides. Results Peptide AA81008-19-30 had excellent and acceptable diagnostic performances for discriminating S. mansoni and S. haematobium positives from healthy controls, with AUC values of 0.8043 and 0.7326 respectively for IgG. Peptides MS3_10186-123-131, MS3_10385-339-354, SmSPI-177-193, SmSPI-379-388, MS3-10186-40-49 and SmS-197-214 had acceptable diagnostic performances for discriminating S. mansoni positives from healthy controls with AUC values ranging from 0.7098 to 0.7763 for IgG. Peptides SmSPI-359-372, Smp126160-438-452 and MS3 10186-25-41 had acceptable diagnostic performances for discriminating S. mansoni positives from S. mansoni negatives with AUC values of 0.7124, 0.7156 and 0.7115 respectively for IgG. Peptide MS3-10186-40-49 had an acceptable diagnostic performance for discriminating S. mansoni positives from healthy controls, with an AUC value of 0.7413 for IgM. Conclusion One peptide with a good diagnostic performance and nine peptides with acceptable diagnostic performances were identified using the immunoinformatic approach and peptide microarray validation. There is need for evaluation of the peptides with true negatives and a good standard positive reference.
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Modrušan, Matija, Lucija Glazer, Lucija Otmačić, Ivo Crnolatac, Nikola Cindro, Nikolina Vidović, Ivo Piantanida, Giovanna Speranza, Gordan Horvat, and Vladislav Tomišić. "Anion-Binding Properties of Short Linear Homopeptides." International Journal of Molecular Sciences 25, no. 10 (May 11, 2024): 5235. http://dx.doi.org/10.3390/ijms25105235.
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A comprehensive thermodynamic and structural study of the complexation affinities of tetra (L1), penta (L2), and hexaphenylalanine (L3) linear peptides towards several inorganic anions in acetonitrile (MeCN) and N,N-dimethylformamide (DMF) was carried out. The influence of the chain length on the complexation thermodynamics and structural changes upon anion binding are particularly addressed here. The complexation processes were characterized by means of spectrofluorimetric, 1H NMR, microcalorimetric, and circular dichroism spectroscopy titrations. The results indicate that all three peptides formed complexes of 1:1 stoichiometry with chloride, bromide, hydrogen sulfate, dihydrogen phosphate (DHP), and nitrate anions in acetonitrile and DMF. In the case of hydrogen sulfate and DHP, anion complexes of higher stoichiometries were observed as well, namely those with 1:2 and 2:1 (peptide:anion) complexes. Anion-induced peptide backbone structural changes were studied by molecular dynamic simulations. The anions interacted with backbone amide protons and one of the N-terminal amine protons through hydrogen bonding. Due to the anion binding, the main chain of the studied peptides changed its conformation from elongated to quasi-cyclic in all 1:1 complexes. The accomplishment of such a conformation is especially important for cyclopeptide synthesis in the head-to-tail macrocyclization step, since it is most suitable for ring closure. In addition, the studied peptides can act as versatile ionophores, facilitating transmembrane anion transport.
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Wang, Guangshun. "Bioinformatic Analysis of 1000 Amphibian Antimicrobial Peptides Uncovers Multiple Length-Dependent Correlations for Peptide Design and Prediction." Antibiotics 9, no. 8 (August 7, 2020): 491. http://dx.doi.org/10.3390/antibiotics9080491.
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Amphibians are widely distributed on different continents, except for the polar regions. They are important sources for the isolation, purification and characterization of natural compounds, including peptides with various functions. Innate immune antimicrobial peptides (AMPs) play a critical role in warding off invading pathogens, such as bacteria, fungi, parasites, and viruses. They may also have other biological functions such as endotoxin neutralization, chemotaxis, anti-inflammation, and wound healing. This article documents a bioinformatic analysis of over 1000 amphibian antimicrobial peptides registered in the Antimicrobial Peptide Database (APD) in the past 18 years. These anuran peptides were discovered in Africa, Asia, Australia, Europe, and America from 1985 to 2019. Genomic and peptidomic studies accelerated the discovery pace and underscored the necessity in establishing criteria for peptide entry into the APD. A total of 99.9% of the anuran antimicrobial peptides are less than 50 amino acids with an average length of 24 and a net charge of +2.5. Interestingly, the various amphibian peptide families (e.g., temporins, brevinins, esculentins) can be connected through multiple length-dependent relationships. With an increase in length, peptide net charge increases, while the hydrophobic content decreases. In addition, glycine, leucine, lysine, and proline all show linear correlations with peptide length. These correlations improve our understanding of amphibian peptides and may be useful for prediction and design of new linear peptides with potential applications in treating infectious diseases, cancer and diabetes.
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Calvo-Calle, J. Mauricio, Giane A. Oliveira, Carol Othoro Watta, Jonathan Soverow, Carlos Parra-Lopez, and Elizabeth H. Nardin. "A Linear Peptide Containing Minimal T- and B-Cell Epitopes of Plasmodium falciparum Circumsporozoite Protein Elicits Protection against Transgenic Sporozoite Challenge." Infection and Immunity 74, no. 12 (October 9, 2006): 6929–39. http://dx.doi.org/10.1128/iai.01151-06.
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ABSTRACT An effective malaria vaccine is needed to address the public health tragedy resulting from the high levels of morbidity and mortality caused by Plasmodium parasites. The first protective immune mechanism identified in the irradiated sporozoite vaccine, the “gold standard” for malaria preerythrocytic vaccines, was sporozoite-neutralizing antibody specific for the repeat region of the surface circumsporozoite (CS) protein. Previous phase I studies demonstrated that a branched peptide containing minimal T- and B-cell epitopes of Plasmodium falciparum CS protein elicited antirepeat antibody and CD4+-T-cell responses comparable to those observed in volunteers immunized with irradiated P. falciparum sporozoites. The current study compares the immunogenicity of linear versus tetrabranched peptides containing the same minimal T- and B-cell epitopes, T1BT*, comprised of a CS-derived universal Th epitope (T*) synthesized in tandem with the T1 and B repeats of P. falciparum CS protein. A simple 48-mer linear synthetic peptide was found to elicit antisporozoite antibody and gamma interferon-secreting T-cell responses comparable to the more complex tetrabranched peptides in inbred strains of mice. The linear peptide was also immunogenic in outbred nonhuman primates (Aotus nancymaae), eliciting antibody titers equivalent to those induced by tetrabranched peptides. Importantly, the 48-mer linear peptide administered in adjuvants suitable for human use elicited antibody-mediated protection against challenge with rodent malaria transgenic sporozoites expressing P. falciparum CS repeats. These findings support further evaluation of linear peptides as economical, safe, and readily produced malaria vaccines for the one-third of the world's population at risk of malaria infection.
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Gisemba, Solomon A., Michael J. Ferracane, Thomas F. Murray, and Jane V. Aldrich. "A Bicyclic Analog of the Linear Peptide Arodyn Is a Potent and Selective Kappa Opioid Receptor Antagonist." Molecules 29, no. 13 (June 29, 2024): 3109. http://dx.doi.org/10.3390/molecules29133109.
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Kappa opioid receptor (KOR) antagonists have potential therapeutic applications in the treatment of stress-induced relapse to substance abuse and mood disorders. The dynorphin A analog arodyn (Ac[Phe1,2,3,Arg4,D-Ala8]dynorphin A-(1–11)-NH2) exhibits potent and selective kappa opioid receptor antagonism. Multiple cyclizations in longer peptides, such as dynorphin and its analogs, can extend the conformational constraint to additional regions of the peptide beyond what is typically constrained by a single cyclization. Here, we report the design, synthesis, and pharmacological evaluation of a bicyclic arodyn analog with two constraints in the opioid peptide sequence. The peptide, designed based on structure–activity relationships of monocyclic arodyn analogs, was synthesized by solid-phase peptide synthesis and cyclized by sequential ring-closing metathesis (RCM) in the C- and N-terminal sequences. Molecular modeling studies suggest similar interactions of key aromatic and basic residues in the bicyclic peptide with KOR as found in the cryoEM structure of KOR-bound dynorphin, despite substantial differences in the backbone conformations of the two peptides. The bicyclic peptide’s affinities at KOR and mu opioid receptors (MOR) were determined in radioligand binding assays, and its KOR antagonism was determined in the [35S]GTPγS assay in KOR-expressing cells. The bicyclic analog retains KOR affinity and selectivity (Ki = 26 nM, 97-fold selectivity over MOR) similar to arodyn and exhibits potent KOR antagonism in the dynorphin-stimulated [35S]GTPγS assay. This bicyclic peptide represents a promising advance in preparing cyclic opioid peptide ligands and opens avenues for the rational design of additional bicyclic opioid peptide analogs.
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Schönberger, Nora, Christina Zeitler, Robert Braun, Franziska L. Lederer, Sabine Matys, and Katrin Pollmann. "Directed Evolution and Engineering of Gallium-Binding Phage Clones—A Preliminary Study." Biomimetics 4, no. 2 (May 8, 2019): 35. http://dx.doi.org/10.3390/biomimetics4020035.
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The phage surface display technology is a useful tool to screen and to extend the spectrum of metal-binding protein structures provided by nature. The directed evolution approach allows identifying specific peptide ligands for metals that are less abundant in the biosphere. Such peptides are attractive molecules in resource technology. For example, gallium-binding peptides could be applied to recover gallium from low concentrated industrial wastewater. In this study, we investigated the affinity and selectivity of five bacteriophage clones displaying different gallium-binding peptides towards gallium and arsenic in independent biosorption experiments. The displayed peptides were highly selective towards Ga3+ whereby long linear peptides showed a lower affinity and specificity than those with a more rigid structure. Cysteine scanning was performed to determine the relationship between secondary peptide structure and gallium sorption. By site-directed mutagenesis, the amino acids of a preselected peptide sequence are systematically replaced by cysteines. The resulting disulphide bridge considerably reduces the flexibility of linear peptides. Subsequent biosorption experiments carried out with the mutants obtained from cysteine scanning demonstrated, depending on the position of the cysteines in the peptide, either a considerable increase in the affinity of gallium compared to arsenic or an increase in the affinity for arsenic compared to gallium. This study shows the impressive effect on peptide–target interaction based on peptide structure and amino acid position and composition via the newly established systematic cysteine scanning approach.
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Singh, Niraj K., Anuj Tyagi, Sumit Singhal, Anjay, Yogendra Singh Jadoun, and Anuradha Kumari. "Bio-Computational Prediction of Novel Epitopes on VP2 Protein of Infectious Bursal Disease Virus." Journal of Advances in Microbiology 24, no. 5 (June 2, 2024): 26–39. http://dx.doi.org/10.9734/jamb/2024/v24i5824.
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Aim: Recently, many viral Immunogenic peptides or epitopes have been used as potential vaccine and also immuno-diagnostic candidates. In this study, we predicted different epitopic peptides on VP2 protein of infectious bursal disease virus (IBDV) using bioinformatics tools, which can be potential vaccine as well as diagnostic candidate for IBD, in future. Study Design: In the present study, B-cell epitopes (linear or continuous, and conformational) and T-cell epitopes were predicted on VP2 protein. Place and Duration of Study: Bihar Animal Sciences University, Patna, and Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana, India between June and December 2023. Methodology: For the prediction of linear B-cell epitopes, Bepipred Linear Epitope Prediction 2.0, SVMTriP, and BCPred tools were used, while Ellipro was used for conformational B-cell epitopes prediction. In the absence of immune-bioinformatics tool is available to predict poultry MHC-peptide binding, only those human MHC-I/II alleles having greater than 70% identities those of poultry MHC-I/II alleles were selected. NetMHCcons 1.1 and NetMHCIIpan - 4.0 tools were used to predict strong binding affinity of peptides with MHC-I and MHC-II, respectively. Results: As per analysis by four different tools, the peptide ‘SYDLGYVRLGDPIPAIGLDPKMV ATCDSSDRPRVYTITAADDYQFSSQYQPGGV164-217’ (EpitopeL) was predicted as the most prominent linear B-cell epitope. Two peptides, i.e. ANLNSPLKIAG (EpitopeC 1) and SSQYQPGGRTSVHGLGLTTGTDKSGGQAGDQMS (EpitopeC 2) were predicted as potent conformational B-cell epitopes. During T-cell epitopes prediction, human HLA*B 40:06, HLA*B 41:03 and HLA*B 41:04 alleles chosen as homologues of poultry MHC class I alleles while DRB1:1310, DRB1:1366, DRB1:1445, and DRB1:1482 chosen as homologues of poultry MHC class II alleles. A 9-mer GELVFQTSV236-244 peptide was predicted as MHC-I strong binder ability while, two 15-mer peptides, i.e. YTKLILSERDRLGIK389-403 and QMLLTAQNLPASYNY76-90 were predicted as MHC-II strong binder ability. Conclusion: Using bio-computational analysis, one linear and two conformational B-cell epitopes were predicted on VP2 protein of IBDV. During T-cell epitopes prediction one 9-mer peptide and two 15-mer peptides were predicted as MHC-I and MHC-II strong binding peptides, respectively. After assessing protective immune responses through in vitro and in vivo studies, these predicted peptides could be potential candidates for developing subunit vaccines.
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Hlaváček, Jan, Otto Smékal, Jan Pospíšek, and Tomislav Barth. "Synthesis of Peptides Influencing Growth Hormone Release." Collection of Czechoslovak Chemical Communications 59, no. 3 (1994): 707–17. http://dx.doi.org/10.1135/cccc19940707.
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A solid phase peptide synthesis of 17 growth hormone (GH) releasing peptide analogues Ia - IIIc for their use in a pharmacological assay on GH release is described. While the linear peptide amides Ia - Ij were synthesized on p-methylbenzhydrylamine resin using Boc strategy, and cleaved by HF in the presence of scavengers the linear peptide amides Ik and Il were prepared on Merrifield benzyl ester type resin using Fmoc strategy and cleaved by ammonolysis. The deleted peptide amides IIa and IIb were obtained as by-products during HPLC purification of analogues Ic and Id. The linear precursors of cyclic peptides IIIa - IIIc were also prepared on Merrifield resin and cleaved under mild alkaline conditions. Their cyclization was performed in solution by diphenylphosphoryl azide.
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Davies, Matthew N., and Darren R. Flower. "A Benchmark Dataset Comprising Partition and Distribution Coefficients of Linear Peptides." Dataset Papers in Biology 2013 (May 16, 2013): 1–4. http://dx.doi.org/10.7167/2013/976758.
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Peptides have a dominant role in biology; yet the study of their physical properties is at best sporadic. Peptide quantitative structure-activity relationship (QSAR) lags far behind the QSAR analysis of drug-like organic small molecules. Traditionally, QSAR has focussed on experimentally determined partition coefficients as the main descriptor of hydrophobicity. A partition coefficient () is the ratio between the concentrations of an uncharged chemical substance in two immiscible phases: most typically water and an organic solvent, usually 1-octanol. A distribution coefficient () is the equivalent ratio for charged molecules. We report here a compilation of partition and distribution coefficients for linear peptides compiled from literature reports, suitable for the development and benchmarking of peptide and prediction algorithms.
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Zheng, Mengjun, Ruina Wang, Si Chen, Yan Zou, Lan Yan, Linjing Zhao, and Xiang Li. "Design, Synthesis and Antifungal Activity of Stapled Aurein1.2 Peptides." Antibiotics 10, no. 8 (August 9, 2021): 956. http://dx.doi.org/10.3390/antibiotics10080956.
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Aurein1.2 is a 13-residue antimicrobial peptide secreted by the Australian tree frog Litoria aurea. In order to improve its stabilities, the helical contents and corresponding biological activities of Aurein1.2 (a series of stapled analogues) were synthesized, and their potential antifungal activities were evaluated. Not surprisingly, the stapled Aurein1.2 peptides showed higher proteolytic stability and helicity than the linear counterpart. The minimum inhibitory concentration (MIC) of ten stapled peptides against six strains of common pathogenic fungi was determined by the microscale broth dilution method recommended by CLSI. Of them, Sau-1, Sau-2, Sau-5, and Sau-9 exhibited better inhibitory effects on the fungi than the linear peptide. These stapled Aurein1.2 peptides may serve as the leading compounds for further optimization and antifungal therapy.
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Franke, E. D., G. Corradin, and S. L. Hoffman. "Induction of protective CTL responses against the Plasmodium yoelii circumsporozoite protein by immunization with peptides." Journal of Immunology 159, no. 7 (October 1, 1997): 3424–33. http://dx.doi.org/10.4049/jimmunol.159.7.3424.
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Abstract To determine the optimum combination, concentration, and formulation of synthetic peptides and adjuvants to induce protective CTL responses against the Plasmodium yoelii circumsporozoite protein (PyCSP), BALB/c mice were immunized with linear and multiple antigen peptides (MAP) including PyCSP CTL and Th epitopes in Montanide's ISA51, Lipofectin, and Lipofectamine. An H-2K(d)-restricted PyCSP CTL epitope, SYVPSAEQI (amino acids (aa) 280-288), recognized by protective CTL clones, was included in the following peptides: a 9-aa linear peptide (SYVPSAEQI; PyCSP9), a 20-aa linear peptide (aa 280-299; SYVPSAEQILEFVKQISSL; PyCSP20), a MAP containing four branches of PyCSP20 (MAP(280-299)), and a linear peptide and a MAP(MAP(280-299)p2p30) in which PyCSP20 was colinearly synthesized with two universal Th epitopes from tetanus toxin (p2p30). A MAP containing the PyCSP Th epitope (aa 57-70; KIYNRNIVNRLLGD) was included in some experiments. The highest specific lytic activity against peptide-pulsed target cells was obtained with splenocytes from mice immunized with three doses at 3-wk intervals of MAP(280-299)p2p30 in Lipofectin or Lipofectamine. Forty percent of the mice immunized with MAP(280-299)p2p30 and Lipofectin were protected against sporozoite challenge. Immunization with CTL and Th epitopes co-linearly synthesized in a MAP induced significantly better CTL than did immunization with the same sequence as a linear peptide, or immunization with a mixture of two individual MAPs, one with the CTL epitope and the second with the Th epitope.
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Shatilov, A. A., S. M. Andreev, A. V. Shatilova, E. A. Turetskiy, R. A. Kurmasheva, M. O. Babikhina, L. V. Saprigina, et al. "Synthesis of plyphenol-containing cationic linear and dendrimeric peptides with anti-oxidant activity." Биохимия 89, no. 1 (July 31, 2024): 182–93. http://dx.doi.org/10.31857/10.31857/s0320972524010105.
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Natural polyphenols are of great interest from the point of view of their use for the pharmacological control of oxidative stress and many diseases. However, the low bioavailability and rapid metabolism of polyphenols in the form of glycosides or aglycones stimulates the search for effective means of delivery into systemic circulation. Conjugation of polyphenols with cationic amphiphilic peptides can result in compounds with strong antioxidant activity and the ability to cross biological barriers. Such compounds may be in demand as drugs for antioxidant therapy, including for the treatment of viral, oncological and neurodegenerative diseases due to the diverse range of biological activities inherent in polyphenols and peptides. In this work, cationic linear and dendrimer amphiphilic cationic peptides were synthesized by the solid phase method, and a number of peptides were conjugated to gallic acid (Ga). Ga is a non-toxic natural phenolic acid and an important functional element of many flavonoids with high antioxidant activity. It was shown that the resulting Ga-peptide conjugates exhibited antioxidant (antiradical) activity that was 2-3 times higher than that of ascorbic acid. Other tests indicated that the addition of Ga did not affect the toxicity and hemolytic activity of the conjugates. Ga-modified peptides stimulated the transmembrane transfer of the pGL3 plasmid encoding the luciferase reporter gene; however, the addition of Ga to the N-terminus of the peptide reduced its transfection activity. Some of the resulting compounds had noticeable inhibitory activity against theE. сoli-Dh5α strain.
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Jankowska, Dżesika, Wiktoria Rejmak, Adam Lesner, and Natalia Gruba. "PEPTYDY Z WĘZŁEM CYSTEINOWYM JAKO INHIBITORY KALLIKREINY 13." Wiadomości Chemiczne 78, no. 3 (March 18, 2024): 345–68. https://doi.org/10.53584/wiadchem.2024.03.9.
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nhibitor cysteine knots (ICK) also known as "knottins," are cysteine-rich peptides typically composed of approximately 30 amino acids. These peptides exhibit a characteristic robust structure featuring three antiparallel β-sheets that are "knotted" together by three disulfide bonds. This structural motif confers stability to the protein, rendering it resistant to thermal denaturation and proteolysis. Consequently, inhibitor cysteine knots hold great promise as scaffolds for developing new peptide drugs. In this study, we present the synthesis and evaluation of six potential inhibitors targeting KLK13, utilizing the Ecballium elaterium trypsin II inhibitor (EETI-II) as the leading structure. The peptides were synthesized in solid-phase peptide synthesis with an automated peptide synthesizer. Subsequently, they were oxidized using iodine and then quenched with an anion exchange resin. Both linear and oxidized compounds were obtained and subjected to kinetic studies. The inhibitory activity against KLK13 was observed exclusively in the oxidized analogues of the synthesized compounds. Linear peptides exhibited lower affinity towards KLK13, highlighting the critical role of the disulfide bridge in the structure of the EETI-II analogues for inhibiting the enzyme activity.
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Gao, B., and M. P. Esnouf. "Multiple interactive residues of recognition: elucidation of discontinuous epitopes with linear peptides." Journal of Immunology 157, no. 1 (July 1, 1996): 183–88. http://dx.doi.org/10.4049/jimmunol.157.1.183.
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Abstract The discontinuous epitopes of beta-factor XIIa for three mAbs were mapped by a linear peptide-based immunoblotting technique, referred to as multiple interactive residues of recognition. The Abs were incubated with a set of overlapping synthetic peptides, deduced from the cDNA sequences of beta-factor XIIa, on a polymer membrane, and the signal was amplified by an ECL assay. Several discrete sequences of the protein were recognized by each Ab. The recognized peptides were further characterized using alanine substitution analogues and peptides of different lengths. The discontinuous epitopes found for each Ab were formed by several peptides and were composed of 20 to 31 residues. The sequence FLQEA was recognized by all three Abs and was the immunodominant peptide. Abs 201/9 and 2/15 bound to very similar discontinuous sequences, but with subtle differences. The sequences 76RLHEAFSP83, 88HDLALLRLQE97, 178GFLEG182, 146FLQEA150, and 237IRE239 formed the epitope for mAb 201/9, whereas 76RLHEAFSP83, 90LALLRLQE97, 146FLQEA150, and 235AWIREHT241 formed the epitope for Ab 2/15. The third Ab 202/7 recognized the sequences 79EAFSP83, 93LRLQE97, 133WGHQF137, and 146FLQEA150. We suggest that these sequences represent the sites to which the Abs bind. This procedure provides a sensitive and convenient tool to elucidate discontinuous epitopes for the binding of Abs, receptor ligand-binding sites, or enzyme inhibitor binding sites.
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Dockal, Michael, Rudolf Hartmann, Thomas Polakowski, Christoph Redl, Erwin Panholzer, Willibald Kammlander, Frank Osterkamp, Ulrich Reineke, Hans Brandstetter, and Friedrich Scheiflinger. "Molecular Characterization of the Synergistic Effect on TFPI Inhibition By Fusion of Two Inhibitory Peptides." Blood 124, no. 21 (December 6, 2014): 1484. http://dx.doi.org/10.1182/blood.v124.21.1484.1484.
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Abstract Introduction Tissue factor pathway inhibitor (TFPI) is a three-Kunitz domain (KD1-3) protease inhibitor that downregulates the extrinsic coagulation pathway. TFPI has a double inhibitory effect; it inactivates factor Xa (FXa) by 1:1 binding via its KD2, and it prevents further FX activation by binding the tissue factor (TF) – factor VIIa (FVIIa) complex via its KD1 and the formation of a quaternary complex. Recently, we demonstrated the crystal structure of a linear TFPI inhibitory peptide composed of 20 amino acids, bound to a TFPI protein composed of N-terminus and KD1. On the other hand, a cyclic TFPI inhibitory peptide of 23 amino acids was shown to co-crystallize with TFPI KD1-KD2. Molecular fusion of the linear and cyclic peptide by an optimized linker sequence would thus target two independent epitopes and combine the antagonistic properties of the two peptides. Methods The binding properties of simultaneous interaction of the linear and cyclic peptide with TFPI were studied in Biacore experiments using immobilized human TFPI 1-160 on a CM5 chip. Measurements with the linear or cyclic peptide were done with and without prior saturation of TFPI with the linear peptide and the fusion peptide. The results were confirmed by native-PAGE analysis of peptide/KD1-KD2 mixtures, where the TFPI fragment KD1-KD2 had been incubated with either linear or cyclic peptide or both. The TFPI inhibitory effect of the linear, cyclic, and fusion peptide was assessed in several TFPI sensitive assays including inhibition of FXa, FX activation by TF/FVIIa, and thrombin generation. Calibrated automated thrombography (CAT) was performed in human hemophilia plasma triggered with low tissue factor. To model a situation of elevated plasma levels of TFPI, the assay was carried out at TFPI concentrations up to 10 nM, which is 40-fold higher than the physiological TFPI plasma concentration. Results Biacore binding studies demonstrated that binding kinetics of the cyclic peptide to TFPI 1-160 were not influenced by prior saturation of immobilized TFPI with the linear peptide and vice versa. Prior saturation of immobilized TFPI with the fusion peptide prohibited the linear and cyclic peptide from binding to TFPI, clearly demonstrating the independent binding of the two peptides to different epitopes. By native-PAGE, the linear peptide shifted the KD1-KD2 band completely, whereas the cyclic peptide shifted it only partially. In the presence of both peptides, KD1-KD2 shifted to the highest MW to charge ratio, indicating the formation of a ternary complex consisting of K1-K2, cyclic, and linear peptide. Although the linear and cyclic peptide inhibited TFPI in functional assays, fusion of the two molecular entities provided the most efficient inhibition of TFPI. This was most evident in assays involving multiple epitopes of TFPI to provide functions such as inhibition of extrinsic FX activation complex and thrombin generation, or at high TFPI concentrations. Thrombin generation assays using of 5- to 40-fold elevated TFPI showed that, separately, the two monomeric peptides are only partial inhibitors, and that a mixture of these peptides led to an improved response. However, molecular fusion of the two entities resulted in the most efficient TFPI neutralization. Thus, a synergistic effect is achieved by linking both peptides. Importantly, thrombin generation compromised by a 40-fold of normal TFPI level is normalized by fusion peptide concentrations as low as 50 nM. Summary Based on structural information, we developed a peptide inhibitor composed of two TFPI inhibitory entities. Binding studies support an independent binding mode to non-overlapping binding sites without allosteric cross-talk between binding sites. This introduces synergistic improvement of binding and functional inhibition by bivalent interaction with TFPI. This optimized fusion peptide facilitates efficient TFPI neutralization and resistance to highly increased TFPI levels. Our results further support the use of a fusion peptide in the development of subcutaneous treatment for patients with hemophilia including those with inhibitors. Disclosures Dockal: Baxter Innovations GmbH, Vienna, Austria: Employment. Hartmann:Baxter Innovations GmbH, Vienna, Austria: Employment. Polakowski:3B Pharmaceuticals GmbH, Berlin, Germany: Employment. Redl:Baxter Innovations GmbH, Vienna, Austria: Employment. Panholzer:Baxter Innovations GmbH, Vienna, Austria: Employment. Kammlander:Baxter Innovations GmbH: Employment. Osterkamp:3B Pharmaceuticals, Berlin, Germany: Employment. Reineke:3B Pharmaceuticals GmbH, Berlin, Germany: Employment. Brandstetter:Department of Molecular Biology, University of Salzburg, Salzburg, Austria: Research Funding. Scheiflinger:Baxter Innovations GmbH, Vienna, Austria: Employment.
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Söylemez, Ümmü Gülsüm, Malik Yousef, Zülal Kesmen, Mine Erdem Büyükkiraz, and Burcu Bakir-Gungor. "Prediction of Linear Cationic Antimicrobial Peptides Active against Gram-Negative and Gram-Positive Bacteria Based on Machine Learning Models." Applied Sciences 12, no. 7 (April 3, 2022): 3631. http://dx.doi.org/10.3390/app12073631.
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Antimicrobial peptides (AMPs) are considered as promising alternatives to conventional antibiotics in order to overcome the growing problems of antibiotic resistance. Computational prediction approaches receive an increasing interest to identify and design the best candidate AMPs prior to the in vitro tests. In this study, we focused on the linear cationic peptides with non-hemolytic activity, which are downloaded from the Database of Antimicrobial Activity and Structure of Peptides (DBAASP). Referring to the MIC (Minimum inhibition concentration) values, we have assigned a positive label to a peptide if it shows antimicrobial activity; otherwise, the peptide is labeled as negative. Here, we focused on the peptides showing antimicrobial activity against Gram-negative and against Gram-positive bacteria separately, and we created two datasets accordingly. Ten different physico-chemical properties of the peptides are calculated and used as features in our study. Following data exploration and data preprocessing steps, a variety of classification algorithms are used with 100-fold Monte Carlo Cross-Validation to build models and to predict the antimicrobial activity of the peptides. Among the generated models, Random Forest has resulted in the best performance metrics for both Gram-negative dataset (Accuracy: 0.98, Recall: 0.99, Specificity: 0.97, Precision: 0.97, AUC: 0.99, F1: 0.98) and Gram-positive dataset (Accuracy: 0.95, Recall: 0.95, Specificity: 0.95, Precision: 0.90, AUC: 0.97, F1: 0.92) after outlier elimination is applied. This prediction approach might be useful to evaluate the antibacterial potential of a candidate peptide sequence before moving to the experimental studies.
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Botti, Paolo, T. David Pallin, and James P. Tam. "Cyclic Peptides from Linear Unprotected Peptide Precursors through Thiazolidine Formation†." Journal of the American Chemical Society 118, no. 42 (January 1996): 10018–24. http://dx.doi.org/10.1021/ja954278g.
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Sharma, Ravi D., Jainendra Jain, and Ratan L. Khosa. "Design, Synthesis and Anticancer Activity of Site Specific Short Chain Cationic Peptide." Current Drug Discovery Technologies 17, no. 5 (December 23, 2020): 631–46. http://dx.doi.org/10.2174/1570163816666190402121033.
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Background: In spite of current progress in treatment methods, cancer is a major source of morbidity and death rate all over the world. Traditional chemotherapeutic agents aim to divide cancerous cells, are often associated with deleterious side effects to healthy cells and tissues. Host defense peptides Cecropin A and B obtained from insects are capable to lyses various types of human cancer cells at peptide concentrations which are not fatal to normal eukaryotic cells. Methods: In the present work we have designed short chain α-helical linear and cyclic peptide from cecropin A having same cationic charge, hydrophobicity and helicity. Synthesis of designed novel short chain linear (10) and cyclic compound (12) was accomplished by using solution phase method. All the coupling reactions were carried out by using dicyclohexylcarbodiimide (DCC) as the coupling reagent at room temperature in the presence of N-methylmorpholine (NMM) as the base. The Structure of newly synthesized peptidse were elucidated by 1H-NMR, 13C-NMR, FT-IR, FABMS and elemental analysis data.Cytotoxicity of synthesized compound was tested against Dalton’s Lymphoma Ascites (DLA), Ehrlich’s Ascites Carcinoma (EAC) and MCF-7 cell lines by using MTT assay and 5-FU as reference compound. Results: From biological assessment,it was found that short chain cyclicpeptide12 showed high level of cytotoxic activity against DLA and EAC cell lines. Conclusion: By utilizing a structure-based rational approach to anticancer peptide design from cecropin A, we were able to develop short chain linear and cyclic peptides having same charge, hydrophobicity and with improved activity. Systematically removing amino acids, we were able to retaining peptide charge and hydrophobicity/hydrophilicity in linear and cyclic peptide which results to optimize the anticancer activity against DLA and EAC cell lines.
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Payne, Jennifer A. E., Melanie Schoppet, Mathias Henning Hansen, and Max J. Cryle. "Diversity of nature's assembly lines – recent discoveries in non-ribosomal peptide synthesis." Molecular BioSystems 13, no. 1 (2017): 9–22. http://dx.doi.org/10.1039/c6mb00675b.
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Hoover, David M., Zhibin Wu, Kenneth Tucker, Wuyuan Lu, and Jacek Lubkowski. "Antimicrobial Characterization of Human β-Defensin 3 Derivatives." Antimicrobial Agents and Chemotherapy 47, no. 9 (September 2003): 2804–9. http://dx.doi.org/10.1128/aac.47.9.2804-2809.2003.
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ABSTRACT Human β-defensin 3 (hBD3) is a highly basic 45-amino-acid protein that acts both as an antimicrobial agent and as a chemoattractant molecule. Although the nature of its antimicrobial activity is largely electrostatic, the importance of the molecular structure on this activity is poorly understood. Two isoforms of hBD3 were synthesized: the first with native disulfide linkages and the second with nonnative linkages. In a third synthetic peptide, all cysteine residues were replaced with α-aminobutyric acid, creating a completely linear peptide. A series of six small, linear peptides corresponding to regions of hBD3 with net charges ranging from +4 to +8 (at pH 7) and lengths ranging from 9 to 20 amino acids were also synthesized. The linear full-length peptide showed the highest microbicidal activity against Escherichia coli and Staphylococcus aureus, while all three full-length forms showed equal activity against Candida albicans. The linear peptide also showed high activity against Enterococcus faecium and Pseudomonas aeruginosa. Peptides corresponding to the C terminus showed higher activities when tested against E. coli, with the most active peptides being the most basic. However, only the peptide corresponding to the N terminus of hBD3 showed any activity against S. aureus and C. albicans. Further, N-terminal deletion mutants of native hBD3 showed diminished activities against S. aureus. Thus, the antimicrobial properties of hBD3 derivatives are determined by both charge and structure.
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Perumal, Pandurangan, and Vijaya P. Pandey. "Antimicrobial peptides: the role of hydrophobicity in the alpha helical structure." Journal of Pharmacy & Pharmacognosy Research 1, no. 1 (September 1, 2013): 39–53. http://dx.doi.org/10.56499/jppres13.005_1.2.39.
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The antimicrobial peptides (AMPs) are a class of molecule obtained from plants, insects, animals, and humans. These peptides have been classified into five categories: 1. Anionic peptide, 2. Linear alpha helical cationic peptide, 3. Cationic peptide, 4. Anionic and cationic peptides with disulphide bonds, and 5. Anionic and cationic peptide fragments of larger proteins. Factors affecting AMPs are sequence, size, charge, hydrophobicity, amphipathicity, structure and conformation. Synthesis of these peptides is convenient by using solid phase peptide synthesis by using FMOC chemistry protocol. The secondary structures of three synthetic peptides were determined by circular dichroism. Also, it was compared the stability of the α-helical structure and confirmed the percentage of helix of these peptides by using circular dichroism. Some of these AMPs show therapeutic properties like antimicrobial, antiviral, contraceptive, and anticancer. The formulations of some peptides have been entered into the phase I, II, or III of clinical trials. This article to review briefly the sources, classification, factors affecting AMPs activity, synthesis, characterization, mechanism of action and therapeutic concern of AMPs and mainly focussed on percentage of α-helical structure in various medium.
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Eggimann, Gabriela A., Emilyne Blattes, Stefanie Buschor, Rasomoy Biswas, Stephan M. Kammer, Tamis Darbre, and Jean-Louis Reymond. "Designed cell penetrating peptide dendrimers efficiently internalize cargo into cells." Chem. Commun. 50, no. 55 (2014): 7254–57. http://dx.doi.org/10.1039/c4cc02780a.
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Redesigning linear cell penetrating peptides (CPPs) into a multi-branched topology with short dipeptide branches gave cell penetrating peptide dendrimers (CPPDs) with higher cell penetration, lower toxicity and hemolysis and higher serum stability than linear CPPs.
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Vlaminck, Johnny, Ole Lagatie, Daniel Dana, Zeleke Mekonnen, Peter Geldhof, Bruno Levecke, and Lieven J. Stuyver. "Identification of antigenic linear peptides in the soil-transmitted helminth and Schistosoma mansoni proteome." PLOS Neglected Tropical Diseases 15, no. 4 (April 28, 2021): e0009369. http://dx.doi.org/10.1371/journal.pntd.0009369.
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The scientific community identified non stool-based biomarkers as the way forward to support soil-transmitted helminth (STH; Ascaris lumbricoides, Trichuris trichiura and the hookworms Ancylostoma duodenale and Necator americanus) and schistosome (S. mansoni and S. haematobium) deworming programs. This support is needed in making the decision of whether or not to stop preventive chemotherapy intervention efforts and to ultimately transition towards a post-intervention surveillance phase. We applied a two-step micro-array approach to identify antigenic linear epitopes in the STH and S. mansoni proteomes. In a first experiment, we identified antigenic peptides by applying sera from 24 STH and/or S. mansoni infected Ethiopian children on a high-density peptide microarray containing 3.3 million peptides derived from the complete STH and S. mansoni proteomes. A second array experiment with 170,185 peptides that were recognized in the first array was designed to identify non-specific antibody reactivity by applying sera from 24 healthy individuals from Belgium (a non-endemic country). From this array testing cascade, several peptides were identified for STH but none of them appeared to be unique for one species. We therefore concluded that for STH, none of the peptides revealed to be sufficiently sensitive or species specific. For S. mansoni, some promising peptides were identified prompting future investigation. Based on these results, it is unlikely that linear epitopes would be highly useful in detecting species-specific antibody responses to STH in endemic communities. For S. mansoni, one particular peptide of the micro-exon gene 12 (MEG-12) protein deserves further research. In addition, this study emphasizes the need of well-characterized biobanks for biomarker discovery, particularly when the integration of multiple disease programs is envisioned.
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Rubin, Samuel J. S., Yftah Tal-Gan, Chaim Gilon, and Nir Qvit. "Conversion of Protein Active Regions into Peptidomimetic Therapeutic Leads Using Backbone Cyclization and Cycloscan – How to Do it Yourself!" Current Topics in Medicinal Chemistry 18, no. 7 (July 9, 2018): 556–65. http://dx.doi.org/10.2174/1568026618666180518094322.
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Protein-protein Interactions (PPIs) are particularly important for controlling both physiologic and pathologic biological processes but are difficult to target due to their large and/or shallow interaction surfaces unsuitable for small molecules. Linear peptides found in nature interact with some PPIs, and protein active regions can be used to design synthetic peptide compounds for inhibition of PPIs. However, linear peptides are limited therapeutically by poor metabolic and conformational stability, which can compromise their bioactivity and half-life. Cyclic peptidomimetics (modified peptides) can be used to overcome these challenges because they are more resistant to metabolic degradation and can be engineered to adopt desired conformations. Backbone cyclization is a strategy that we developed to improve drug-like properties of linear peptide leads without jeopardizing the integrity of functionally relevant side-chains. Here, we provide the first description of an entire approach for developing backbone cyclized peptide compounds, based upon two straightforward ‘ABC’ and ‘DEF’ processes. We present practical examples throughout our discussion of revealing active regions important for PPIs and identifying critical pharmacophores, as well as developing backbone cyclized peptide libraries and screening them using cycloscan. Finally, we review the impact of these advances and provide a summary of current ongoing work in the field.