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Autor: Grafiati

Publicado: 14 de marzo de 2023

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Artículos de revistas sobre el tema "MMV Malaria Box"

Müller, Joachim, Pablo A. Winzer, Kirandeep Samby y Andrew Hemphill. "In Vitro Activities of MMV Malaria Box Compounds against the Apicomplexan Parasite Neospora caninum, the Causative Agent of Neosporosis in Animals". Molecules 25, n.º 6 (24 de marzo de 2020): 1460. http://dx.doi.org/10.3390/molecules25061460.

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(1) Background: Neospora caninum is a major cause of abortion in cattle and represents a veterinary health problem of great economic significance. In order to identify novel chemotherapeutic agents for the treatment of neosporosis, the Medicines for Malaria Venture (MMV) Malaria Box, a unique collection of anti-malarial compounds, were screened against N. caninum tachyzoites, and the most efficient compounds were characterized in more detail. (2) Methods: A N. caninum beta-galactosidase reporter strain grown in human foreskin fibroblasts was treated with 390 compounds from the MMV Malaria Box. The IC50s of nine compounds were determined, all of which had been previously been shown to be active against another apicomplexan parasite, Theileria annulata. The effects of three of these compounds on the ultrastructure of N. caninum tachyzoites were further investigated by transmission electron microscopy at different timepoints after initiation of drug treatment. (3) Results: Five MMV Malaria Box compounds exhibited promising IC50s below 0.2 µM. The compound with the lowest IC50, namely 25 nM, was MMV665941. This compound and two others, MMV665807 and MMV009085, specifically induced distinct alterations in the tachyzoites. More specifically, aberrant structural changes were first observed in the parasite mitochondrion, and subsequently progressed to other cytoplasmic compartments of the tachyzoites. The pharmacokinetic (PK) data obtained in mice suggest that treatment with MMV665941 could be potentially useful for further in vivo studies. (4) Conclusions: We have identified five novel compounds with promising activities against N. caninum, the effects of three of these compounds were studies by transmission electron microscopy (TEM). Their modes of action are unknown and require further investigation.

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Allman, Erik L., Heather J. Painter, Jasmeet Samra, Manuela Carrasquilla y Manuel Llinás. "Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways". Antimicrobial Agents and Chemotherapy 60, n.º 11 (29 de agosto de 2016): 6635–49. http://dx.doi.org/10.1128/aac.01224-16.

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ABSTRACTThe threat of widespread drug resistance to frontline antimalarials has renewed the urgency for identifying inexpensive chemotherapeutic compounds that are effective againstPlasmodium falciparum, the parasite species responsible for the greatest number of malaria-related deaths worldwide. To aid in the fight against malaria, a recent extensive screening campaign has generated thousands of lead compounds with low micromolar activity against blood stage parasites. A subset of these leads has been compiled by the Medicines for Malaria Venture (MMV) into a collection of structurally diverse compounds known as the MMV Malaria Box. Currently, little is known regarding the activity of these Malaria Box compounds on parasite metabolism during intraerythrocytic development, and a majority of the targets for these drugs have yet to be defined. Here we interrogated thein vitrometabolic effects of 189 drugs (including 169 of the drug-like compounds from the Malaria Box) using ultra-high-performance liquid chromatography–mass spectrometry (UHPLC-MS). The resulting metabolic fingerprints provide information on the parasite biochemical pathways affected by pharmacologic intervention and offer a critical blueprint for selecting and advancing lead compounds as next-generation antimalarial drugs. Our results reveal several major classes of metabolic disruption, which allow us to predict the mode of action (MoA) for many of the Malaria Box compounds. We anticipate that future combination therapies will be greatly informed by these results, allowing for the selection of appropriate drug combinations that simultaneously target multiple metabolic pathways, with the aim of eliminating malaria and forestalling the expansion of drug-resistant parasites in the field.

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Fong, Kim Y., Rebecca D. Sandlin y David W. Wright. "Identification of β-hematin inhibitors in the MMV Malaria Box". International Journal for Parasitology: Drugs and Drug Resistance 5, n.º 3 (diciembre de 2015): 84–91. http://dx.doi.org/10.1016/j.ijpddr.2015.05.003.

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Wu, Wesley, Zachary Herrera, Danny Ebert, Katie Baska, Seok H. Cho, Joseph L. DeRisi y Ellen Yeh. "A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis". Antimicrobial Agents and Chemotherapy 59, n.º 1 (3 de noviembre de 2014): 356–64. http://dx.doi.org/10.1128/aac.03342-14.

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ABSTRACTThe apicoplast is an essential plastid organelle found inPlasmodiumparasites which contains several clinically validated antimalarial-drug targets. A chemical rescue screen identified MMV-08138 from the “Malaria Box” library of growth-inhibitory antimalarial compounds as having specific activity against the apicoplast. MMV-08138 inhibition of blood-stagePlasmodium falciparumgrowth is stereospecific and potent, with the most active diastereomer demonstrating a 50% effective concentration (EC50) of 110 nM. Whole-genome sequencing of 3 drug-resistant parasite populations from two independent selections revealed E688Q and L244I mutations inP. falciparumIspD, an enzyme in the MEP (methyl-d-erythritol-4-phosphate) isoprenoid precursor biosynthesis pathway in the apicoplast. The active diastereomer of MMV-08138 directly inhibited PfIspD activityin vitrowith a 50% inhibitory concentration (IC50) of 7.0 nM. MMV-08138 is the first PfIspD inhibitor to be identified and, together with heterologously expressed PfIspD, provides the foundation for further development of this promising antimalarial drug candidate lead. Furthermore, this report validates the use of the apicoplast chemical rescue screen coupled with target elucidation as a discovery tool to identify specific apicoplast-targeting compounds with new mechanisms of action.

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López-Arencibia, Atteneri, Ines Sifaoui, María Reyes-Batlle, Carlos J. Bethencourt-Estrella, Desirée San Nicolás-Hernández, Jacob Lorenzo-Morales y José E. Piñero. "Discovery of New Chemical Tools against Leishmania amazonensis via the MMV Pathogen Box". Pharmaceuticals 14, n.º 12 (24 de noviembre de 2021): 1219. http://dx.doi.org/10.3390/ph14121219.

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The protozoan parasite Leishmania causes a spectrum of diseases and there are over 1 million infections each year. Current treatments are toxic, expensive, and difficult to administer, and resistance to them is emerging. In this study, we screened the antileishmanial activity of the Pathogen Box compounds from the Medicine for Malaria Venture against Leishmania amazonensis, and compared their structures and cytotoxicity. The compounds MMV676388 (3), MMV690103 (5), MMV022029 (7), MMV022478 (9) and MMV021013 (10) exerted a significant dose-dependent inhibition effect on the proliferation of L. amazonensis promastigotes and intracellular amastigotes. Moreover, studies on the mechanism of cell death showed that compounds 3 and 5 induced an apoptotic process while the compounds 7, 9 and 10 seem to induce an autophagic mechanism. The present findings underline the potential of these five molecules as novel therapeutic leishmanicidal agents.

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Alemán Resto, Yesmalie y José A. Fernández Robledo. "Identification of MMV Malaria Box Inhibitors of Perkinsus marinus Using an ATP-Based Bioluminescence Assay". PLoS ONE 9, n.º 10 (22 de octubre de 2014): e111051. http://dx.doi.org/10.1371/journal.pone.0111051.

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Mann, Lea, Markus Lang, Philipp Schulze, Jan Henrik Halz, René Csuk, Sophie Hoenke, Rüdiger W. Seidel y Adrian Richter. "Racemization-free synthesis of Nα-2-thiophenoyl-phenylalanine-2-morpholinoanilide enantiomers and their antimycobacterial activity". Amino Acids 53, n.º 8 (14 de julio de 2021): 1187–96. http://dx.doi.org/10.1007/s00726-021-03044-1.

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AbstractNα-2-thiophenoyl-d-phenylalanine-2-morpholinoanilide (MMV688845, IUPAC: N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide) from the Pathogen Box® library (Medicines for Malaria Ventures, MMV) is a promising lead compound for antimycobacterial drug development. Two straightforward synthetic routes to the title compound starting from phenylalanine or its Boc-protected derivative are reported. Employing Boc-phenylalanine as starting material and the T3P® and PyBOP® amide coupling reagents enables racemization-free synthesis, avoiding the need for subsequent separation of the enantiomers. The crystal structure of the racemic counterpart gives insight into the molecular structure and hydrogen bonding interactions in the solid state. The R-enantiomer of the title compound (derived from d-phenylalanine) exhibits activity against non-pathogenic and pathogenic mycobacterial strains, whereas the S-enantiomer is inactive. Neither of the enantiomers and the racemate of the title compound shows cytotoxicity against various mammalian cells.

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Ruecker, A., D. K. Mathias, U. Straschil, T. S. Churcher, R. R. Dinglasan, D. Leroy, R. E. Sinden y M. J. Delves. "A Male and Female Gametocyte Functional Viability Assay To Identify Biologically Relevant Malaria Transmission-Blocking Drugs". Antimicrobial Agents and Chemotherapy 58, n.º 12 (29 de septiembre de 2014): 7292–302. http://dx.doi.org/10.1128/aac.03666-14.

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ABSTRACTMalaria elimination will require interventions that prevent parasite transmission from the human host to the mosquito. Experimentally, this is usually determined by the expensive and laboriousPlasmodium falciparumstandard membrane feeding assay (PfSMFA), which has limited utility for high-throughput drug screening. In response, we developed theP. falciparumdual gamete formation assay (PfDGFA), which faithfully simulates the initial stages of the PfSMFAin vitro. It utilizes a dual readout that individually and simultaneously reports on the functional viability of male and female mature stage V gametocytes. To validate, we screen the Medicines for Malaria Venture (MMV) Malaria Box library with the PfDGFA. Unique to this assay, we find compounds that target male gametocytes only and also compounds with reversible and irreversible activity. Most importantly, we show that compound activity in the PfDGFA accurately predicts activity in PfSMFAs, which validates and supports its adoption into the transmission-stage screening pipeline.

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Hostettler, Isabel, Joachim Müller y Andrew Hemphill. "In VitroScreening of the Open-Source Medicines for Malaria Venture Malaria Box Reveals Novel Compounds with Profound Activities against Theileria annulata Schizonts". Antimicrobial Agents and Chemotherapy 60, n.º 6 (14 de marzo de 2016): 3301–8. http://dx.doi.org/10.1128/aac.02801-15.

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Intracellular schizonts of the apicomplexansTheileria annulataandTheileria parvaimmortalize bovine leukocytes and thereby cause fatal diseases. The hydroxynaphthoquinone buparvaquone is currently the only option for the treatment of theileriosis, and resistance development has been reported. It is therefore tempting to investigate the repurposing of compounds effective against related apicomplexan parasites, such asPlasmodium. Here, we present the results of a screen of 400 compounds included in the open-access Medicines for Malaria Venture (MMV) malaria box on TaC12 cells, a macrophage-derived cell line immortalized byT. annulataschizonts. Using a combination of the classical alamarBlue vitality assay and a recently developed quantitative reverse transcriptase real-time PCR method based on theTheileriaTaSP gene, we have identified 5 compounds, characterized their effects on the ultrastructure of TaC12 cells, and investigated whether they easily induce resistance formation. Two compounds, the quinolinols MMV666022 and MMV666054, have 50% inhibitory concentrations (IC50s) of 0.5 and 0.2 μM on TaC12 cells and 5.3 and 5.2 μM on BoMac cells, respectively. Thus, with therapeutic indexes of 11 and 18, they represent promising leads for further development of antitheilerial chemotherapeutics.

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Boyom, Fabrice F., Patrick V. T. Fokou, Lauve R. Y. Tchokouaha, Thomas Spangenberg, Alvine N. Mfopa, Ruffin M. T. Kouipou, Cedric J. Mbouna, Valerie F. Donkeng Donfack y Paul H. A. Zollo. "Repurposing the Open Access Malaria Box To Discover Potent Inhibitors of Toxoplasma gondii and Entamoeba histolytica". Antimicrobial Agents and Chemotherapy 58, n.º 10 (21 de julio de 2014): 5848–54. http://dx.doi.org/10.1128/aac.02541-14.

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ABSTRACTToxoplasmosis and amebiasis are important public health concerns worldwide. The drugs currently available to control these diseases have proven limitations. Therefore, innovative approaches should be adopted to identify and develop new leads from novel scaffolds exhibiting novel modes of action. In this paper, we describe results from the screening of compounds in the Medicines for Malaria Venture (MMV) open access Malaria Box in a search for new anti-Toxoplasmaand anti-Entamoebaagents. Standardin vitrophenotypic screening procedures were adopted to assess their biological activities. Seven anti-Toxoplasmacompounds with a 50% inhibitory concentration (IC50) of <5 μM and selectivity indexes (SI) of >6 were identified. The most interesting compound was MMV007791, a piperazine acetamide, which has an IC50of 0.19 μM and a selectivity index of >157. Also, we identified two compounds, MMV666600 and MMV006861, with modest activities againstEntamoeba histolytica, with IC50s of 10.66 μM and 15.58 μM, respectively. The anti-Toxoplasmacompounds identified in this study belong to scaffold types different from those of currently used drugs, underscoring their novelty and potential as starting points for the development of new antitoxoplasmosis drugs with novel modes of action.

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Tesis sobre el tema "MMV Malaria Box"

Galusic, Sandra. "MMV Malaria Box Activity Screening in Dormant Plasmodium falciparum Phenotypes". Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/5687.

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The causative agent of malignant tertian malaria, Plasmodium falciparum undergoes an arrested growth phenotype of its erythrocytic stage when under drug-stress. Recent artemisinin treatment failures seem to be indicative of such induction followed by recrudescence rather than actual therapeutic failure. Likewise, P. vivax hypnozoites are the prototypic dormants and the latent infections for which they are responsible prove most difficult to treat. Dihydroartemisinin, an artemisinin-derivative, can be used to exploit this mechanism by inducing a dormant state in ring-stage P. falciparum parasites and in turn, their recovery may be used as a screening period for compounds that inhibit or foster growth. Specifically, parasites stably transfected with luciferase were used to quantitatively observe growth (or lack thereof) response of parasites to the phytohormone gibberellic acid and the herbicide, fluridone. Using their behavior as comparative controls, the Medicines for Malaria Venture (MMV) Malaria Box was screened for similar activity. The most active compound, 1,2,3,4-tetrahydroacridin-9-ol a quinoline-derivate caused cells to wake even earlier than expected. Since quinine and other such drugs have historically been most effective in treating malaria, it seems appropriate that such a finding was made. Following this the MMV Box was screened again against uninduced 3D7 parasites to determine if any were capable of causing a dormant response under the hypothesis that such a reaction is a defensive adaptation of P. falciparum. Four compounds were found to be active of which two appear to be inducing dormancy in the second cycle rather than the first akin to DHA. These quiescent periods also appear to be shorter indicating that the latter is more efficient. It is possible that given the length of interaction with artemisinin, P. falciparum is more adept to respond to its derivatives likewise the mechanism of action may be different enough to change the nature of the response.

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Foderaro, Jenna Elizabeth. "Target Identification Strategies for MMV Malaria Box Inhibitors of Toxoplasma gondii Growth". ScholarWorks @ UVM, 2017. http://scholarworks.uvm.edu/graddis/698.

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Small molecule screening is commonly used to discover lead compounds for drug development, but it can also be a powerful way to identify chemical probes for studying biological mechanisms. Our lab uses small molecules to study the mechanisms by which the protozoan parasite Toxoplasma gondii infects and replicates within its hosts. In this work, we employed a fluorescence-based assay to screen the Medicines for Malaria Venture (MMV) Open Access Malaria box for compounds that affect T. gondii growth. The box contains 400 previously identified small-molecule inhibitors of the related parasite, Plasmodium falciparum. We identified 79 hits, including a 2,4-diaminoquinazoline (MMV006169; IC50=1.15µM) that strongly inhibits T. gondii intracellular replication and invasion with no evidence of toxicity to mammalian cells. Extensive structure-activity relationship analyses with T. gondii identified a number of analogs with changed potency and altered effects on replication and invasion. These structure-activity analyses provided the information necessary to synthesize a bivalent chemical inducer of dimerization (CID) containing MMV006169 for use in yeast three-hybrid experiments. Yeast growth competition assays showed that this CID is capable of entering the yeast nucleus, as required for yeast three-hybrid screening. Yeast three-hybrid was used in a targeted format to test the hypothesis that MMV006169 works by inhibiting parasite CDC48, an ATPase involved in trafficking and the degradation of misfolded proteins. Large-scale cDNA library screening by yeast three-hybrid suggests that the compound may instead be working through inhibition of a host cell target. This work has provided insight into how MMV006169 affects the parasite's lytic cycle and generated a testable hypothesis for the biologically relevant target of the compound.

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VALLONE, ALESSANDRA. "INVESTIGATION OF NOVEL THERAPEUTIC TOOLS AGAINST INFECTIOUS DISEASES Part 1. Medicinal Chemistry Investigation of MMV019918 Derivatives as Dual Schizonticide And Gametocytocidal Agents Against Plasmodium falciparum Part 2. Investigation of 5-Aryl-Heterocycles As Potential Inhibitors of Metallo beta-Lactamase Enzymes". Doctoral thesis, Università di Siena, 2017. http://hdl.handle.net/11365/1004943.

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Among infectious diseases, two large groups have great clinical relevance: parasitic and bacterial infections. Belonging to the first category is malaria, caused by the parasite Plasmodium falciparum. Transmission of Plasmodium parasites between humans and Anopheles mosquitoes is one of the most important contributors to the global impact of malaria and to the difficulties encountered in eliminating this parasite1 . Gametocytogenesis, the process by which merozoites switch from asexual replication to produce male and female gametocytes, represents a critical step in malaria transmission and Plasmodium genetic diversity. Still too little is known about the biochemical events that regulate gametocytogenesis and there are few existing drugs able of inhibiting the gametocytes development and block malaria transmission2 . To encourage drug discovery and research, the non-profit foundation Medicines for Malaria Venture (MMV) has provided a library of 400 compounds that present antimalarial activity in the micromolar range, but their molecular targets and mode of action are not necessarily known3 . Here we describe the medchem investigation of one of the most promising hit compound included in this library, MMV019918. MMV019918 has been highlighted in several in vitro studies for its promising antigametocyte activity coupled to activity against schizonts. On the basis of its structure, the synthesis of a new series of compounds with transmission-blocking activity has been designed. It has been found very interesting the activity of one derivative NF2350 which resulted active also in the standard membrane feeding assay (SMFA), to measure subsequent mosquito infection, and which has an improved toxicological profile compared to MMV019918. A further investigation of NF2350 will allow us to optimize the transmission-blocking activity and to indentify its putative target. Regarding bacterial infections, a critical issue to be addressed is bacterial resistance to antibiotics and in particular to β-lactams. Metallo-β-lactamases (MBL) are a family of enzymes involved in the widespread mechanisms of resistance to beta-lactam antibiotics, The diffusion of MBL-producing isolates of Pseudomonas aeruginosa, a bacterial pathogen of primary relevance for both nosocomial and chronic infections of the respiratory tracts in cystic fibrosis patients, is notably increasing in some specific settings. No clinically useful MBLs inhibitors are currently available in therapy3 Here we will present the design, synthesis, and biological investigation of a series of functionalized 2-arylfuran compounds with sub-micromolar antiplasmodial activity, against both asexual and sexual stages. Furthermore, appropriate decoration of this molecular scaffold allowed to obtain activity against some isoforms of MBL (including IMP-1and NDM-1).

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