Статті в журналах: "MMV Malaria Box"

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Müller, Joachim, Pablo A. Winzer, Kirandeep Samby, and 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, no. 6 (March 24, 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, and Manuel Llinás. "Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways." Antimicrobial Agents and Chemotherapy 60, no. 11 (August 29, 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 та David W. Wright. "Identification of β-hematin inhibitors in the MMV Malaria Box". International Journal for Parasitology: Drugs and Drug Resistance 5, № 3 (грудень 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, and Ellen Yeh. "A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis." Antimicrobial Agents and Chemotherapy 59, no. 1 (November 3, 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, and José E. Piñero. "Discovery of New Chemical Tools against Leishmania amazonensis via the MMV Pathogen Box." Pharmaceuticals 14, no. 12 (November 24, 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, and José A. Fernández Robledo. "Identification of MMV Malaria Box Inhibitors of Perkinsus marinus Using an ATP-Based Bioluminescence Assay." PLoS ONE 9, no. 10 (October 22, 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 та Adrian Richter. "Racemization-free synthesis of Nα-2-thiophenoyl-phenylalanine-2-morpholinoanilide enantiomers and their antimycobacterial activity". Amino Acids 53, № 8 (14 липня 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, and M. J. Delves. "A Male and Female Gametocyte Functional Viability Assay To Identify Biologically Relevant Malaria Transmission-Blocking Drugs." Antimicrobial Agents and Chemotherapy 58, no. 12 (September 29, 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, and 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, no. 6 (March 14, 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, and 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, no. 10 (July 21, 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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Kenneth Obiakor, Onyeka Chinwuba Obidiegwu, Keziah Uchechi Ajah, Christian Chidebe, Ajuzie Henry Ogechi, and Ikemefuna Chijioke Uzochukwu. "Discovery of antiadhesins of Helicobacter pylori from existing drugs and medicines for malaria ventures pathogen box compounds." GSC Biological and Pharmaceutical Sciences 20, no. 3 (September 30, 2022): 198–212. http://dx.doi.org/10.30574/gscbps.2022.20.3.0356.

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Background: Helicobacter pylori infection is a worldwide problem with more than half of the world's population in both developed and developing countries are infected with this organism. The best-characterized H. pylori adhesins, Blood group antigen binding Adhesin (BabA) and Sialic acid binding Adhesin (SabA) are virulent factors which facilitate adhesion of the bacteria to the host cells. Methods: We determined the binding affinities of selected existing drugs and medicines for malaria venture pathogen box compounds to H. pylori adhesin receptors by molecular docking simulations. The 3D crystal structures of H. pylori adhesin receptors were obtained from Protein Data Bank (PDB). The receptors were prepared for molecular docking simulations using PyMol 1.3, Chimera 1.9 and AutoDock tools 1.5.6. The 3D structures of the selected existing drugs and Medicines for Malaria Ventures (MMV) pathogen box compounds were obtained from ZINC and PubChem databases. They were prepared for molecular docking simulations using AutoDock tools 1.5.6. Docking protocols were validated by reproducing the PDB crystal structures in silico. Molecular docking simulations were executed with a virtual screening script using AutoDock Vina 1.1.2 on a Linux platform. Results: Entacapone, sildenafil, gemcitabine, tolcapone, rabeprazole, tolazamide, teriflunomide, sulfamethazine, cefotetan, talbutal, mitotane, tolbutamide, piperazine showed higher average binding affinities than the reference compound nitazoxanide molecular dynamics of one front runner with the reference ligand and protein were done at 1000 ps. Rabeprazole showed lower stability than the reference drug after molecular dynamics simulation. Conclusion: The identified existing drugs from molecular docking simulations with higher average binding affinities are predicted as possible H. pylori multi-target antiadhesins.

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Lucantoni, Leonardo, Sandra Duffy, Sophie H. Adjalley, David A. Fidock, and Vicky M. Avery. "Identification of MMV Malaria Box Inhibitors of Plasmodium falciparum Early-Stage Gametocytes Using a Luciferase-Based High-Throughput Assay." Antimicrobial Agents and Chemotherapy 57, no. 12 (September 23, 2013): 6050–62. http://dx.doi.org/10.1128/aac.00870-13.

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ABSTRACTThe design of new antimalarial combinations to treatPlasmodium falciparuminfections requires drugs that, in addition to resolving disease symptoms caused by asexual blood stage parasites, can also interrupt transmission to the mosquito vector. Gametocytes, which are essential for transmission, develop as sexual blood stage parasites in the human host over 8 to 12 days and are the most accessible developmental stage for transmission-blocking drugs. Considerable effort is currently being devoted to identifying compounds active against mature gametocytes. However, investigations on the drug sensitivity of developing gametocytes, as well as screening methods for identifying inhibitors of early gametocytogenesis, remain scarce. We have developed a luciferase-based high-throughput screening (HTS) assay using tightly synchronous stage I to III gametocytes from a recombinantP. falciparumline expressing green fluorescent protein (GFP)-luciferase. The assay has been used to evaluate the early-stage gametocytocidal activity of the MMV Malaria Box, a collection of 400 compounds with known antimalarial (asexual blood stage) activity. Screening this collection against early-stage (I to III) gametocytes yielded 64 gametocytocidal compounds with 50% inhibitory concentrations (IC50s) below 2.5 μM. This assay is reproducible and suitable for the screening of large compound libraries, with an average percent coefficient of variance (%CV) of ≤5%, an average signal-to-noise ratio (S:N) of >30, and a Z′ of ∼0.8. Our findings highlight the need for screening efforts directed specifically against early gametocytogenesis and indicate the importance of experimental verification of early-stage gametocytocidal activity in the development of new antimalarial candidates for combination therapy.

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Buckingham, Steven D., Frederick A. Partridge, Beth C. Poulton, Benjamin S. Miller, Rachel A. McKendry, Gareth J. Lycett, and David B. Sattelle. "Automated phenotyping of mosquito larvae enables high-throughput screening for novel larvicides and offers potential for smartphone-based detection of larval insecticide resistance." PLOS Neglected Tropical Diseases 15, no. 6 (June 3, 2021): e0008639. http://dx.doi.org/10.1371/journal.pntd.0008639.

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Pyrethroid-impregnated nets have contributed significantly to halving the burden of malaria but resistance threatens their future efficacy and the pipeline of new insecticides is short. Here we report that an invertebrate automated phenotyping platform (INVAPP), combined with the algorithm Paragon, provides a robust system for measuring larval motility in Anopheles gambiae (and An. coluzzi) as well as Aedes aegypti with the capacity for high-throughput screening for new larvicides. By this means, we reliably quantified both time- and concentration-dependent actions of chemical insecticides faster than using the WHO standard larval assay. We illustrate the effectiveness of the system using an established larvicide (temephos) and demonstrate its capacity for library-scale chemical screening using the Medicines for Malaria Venture (MMV) Pathogen Box library. As a proof-of-principle, this library screen identified a compound, subsequently confirmed to be tolfenpyrad, as an effective larvicide. We have also used the INVAPP / Paragon system to compare responses in larvae derived from WHO classified deltamethrin resistant and sensitive mosquitoes. We show how this approach to monitoring larval response to insecticides can be adapted for use with a smartphone camera application and therefore has potential for further development as a simple portable field-assay with associated real-time, geo-located information to identify hotspots.

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Rice, Christopher A., Emma V. Troth, A. Cassiopeia Russell, and Dennis E. Kyle. "Discovery of Anti-Amoebic Inhibitors from Screening the MMV Pandemic Response Box on Balamuthia mandrillaris, Naegleria fowleri, and Acanthamoeba castellanii." Pathogens 9, no. 6 (June 16, 2020): 476. http://dx.doi.org/10.3390/pathogens9060476.

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Pathogenic free-living amoebae, Balamuthia mandrillaris, Naegleria fowleri, and several Acanthamoeba species are the etiological agents of severe brain diseases, with case mortality rates > 90%. A number of constraints including misdiagnosis and partially effective treatments lead to these high fatality rates. The unmet medical need is for rapidly acting, highly potent new drugs to reduce these alarming mortality rates. Herein, we report the discovery of new drugs as potential anti-amoebic agents. We used the CellTiter-Glo 2.0 high-throughput screening methods to screen the Medicines for Malaria Ventures (MMV) Pandemic Response Box in a search for new active chemical scaffolds. Initially, we screened the library as a single-point assay at 10 and 1 µM. From these data, we reconfirmed hits by conducting quantitative dose–response assays and identified 12 hits against B. mandrillaris, 29 against N. fowleri, and 14 against A. castellanii ranging from nanomolar to low micromolar potency. We further describe 11 novel molecules with activity against B. mandrillaris, 22 against N. fowleri, and 9 against A. castellanii. These structures serve as a starting point for medicinal chemistry studies and demonstrate the utility of phenotypic screening for drug discovery to treat diseases caused by free-living amoebae.

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Shanley, Harrison T., Aya C. Taki, Joseph J. Byrne, Abdul Jabbar, Tim N. C. Wells, Kirandeep Samby, Peter R. Boag, Nghi Nguyen, Brad E. Sleebs, and Robin B. Gasser. "A High-Throughput Phenotypic Screen of the ‘Pandemic Response Box’ Identifies a Quinoline Derivative with Significant Anthelmintic Activity." Pharmaceuticals 15, no. 2 (February 21, 2022): 257. http://dx.doi.org/10.3390/ph15020257.

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Parasitic nematodes cause diseases in livestock animals and major economic losses to the agricultural industry worldwide. Nematodes of the order Strongylida, including Haemonchus contortus, are particularly important. The excessive use of anthelmintic compounds to treat infections and disease has led to widespread resistance to these compounds in nematodes, such that there is a need for new anthelmintics with distinctive mechanisms of action. With a focus on discovering new anthelmintic entities, we screened 400 chemically diverse compounds within the ‘Pandemic Response Box’ (from Medicines for Malaria Venture, MMV) for activity against H. contortus and its free-living relative, Caenorhabditis elegans—a model organism. Using established phenotypic assays, test compounds were evaluated in vitro for their ability to inhibit the motility and/or development of H. contortus and C. elegans. Dose-response evaluations identified a compound, MMV1581032, that significantly the motility of H. contortus larvae (IC50 = 3.4 ± 1.1 μM) and young adults of C. elegans (IC50 = 7.1 ± 4.6 μM), and the development of H. contortus larvae (IC50 = 2.2 ± 0.7 μM). The favourable characteristics of MMV1581032, such as suitable physicochemical properties and an efficient, cost-effective pathway to analogue synthesis, indicates a promising candidate for further evaluation as a nematocide. Future work will focus on a structure-activity relationship investigation of this chemical scaffold, a toxicity assessment of potent analogues and a mechanism/mode of action investigation.

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Rollin-Pinheiro, Rodrigo, Mariana Ingrid Dutra da Silva Xisto, Yuri de Castro-Almeida, Victor Pereira Rochetti, Luana Pereira Borba-Santos, Yasmin da Silva Fontes, Antonio Ferreira-Pereira, Sonia Rozental, and Eliana Barreto-Bergter. "Pandemic Response Box® library as a source of antifungal drugs against Scedosporium and Lomentospora species." PLOS ONE 18, no. 2 (February 3, 2023): e0280964. http://dx.doi.org/10.1371/journal.pone.0280964.

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Scedosporium and Lomentospora species are opportunistic filamentous fungi that cause localized and disseminated infections in immunocompetent and immunocompromised patients. These species are considered resistant fungi due to their low susceptibility to most current antifungal agents used in healthcare settings. The search for new compounds that could work as promising candidate antifungal drugs is an increasing field of interest. In this context, in the present study we screened the Pandemic Response Box® library (Medicines for Malaria Venture [MMV], Switzerland) to identify compounds with antifungal activity against Scedosporium and Lomentospora species. An initial screening of the drugs from this collection at 5 μM was performed using a clinical Scedosporium aurantiacum isolate according to the EUCAST protocol. Compounds with activity against this fungus were also tested against four other species (S. boydii¸ S. dehoogii, S. apiospermum and L. prolificans) at concentrations ranging from 0.078 to 10 μM. Seven compounds inhibited more than 80% of S. aurantiacum growth, three of them (alexidine, amorolfine and olorofim) were selected due to their differences in mechanism of action, especially when compared to drugs from the azole class. These compounds were more active against biofilm formation than against preformed biofilm in Scedosporium and Lomentospora species, except alexidine, which was able to decrease preformed biofilm about 50%. Analysis of the potential synergism of these compounds with voriconazole and caspofungin was performed by the checkerboard method for S. aurantiacum. The analysis by Bliss methodology revealed synergistic effects among selected drugs with caspofungin. When these drugs were combined with voriconazole, only alexidine and amorolfine showed a synergistic effect, whereas olorofim showed an antagonistic effect. Scanning electron microscopy revealed that alexidine induces morphology alterations in S. aurantiacum biofilm grown on a catheter surface. Reactive oxygen species production, mitochondrial activity and surface components were analyzed by fluorescent probes when S. aurantiacum was treated with selected drugs and revealed that some cell parameters are altered by these compounds. In conclusion, alexidine, amorolfine and olorofim were identified as promising compounds to be studied against scedosporiosis and lomentosporiosis.

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Rice, Christopher A., Luis Fernando Lares-Jiménez, Fernando Lares-Villa, and Dennis E. Kyle. "In Vitro Screening of the Open-Source Medicines for Malaria Venture Malaria and Pathogen Boxes To Discover Novel Compounds with Activity against Balamuthia mandrillaris." Antimicrobial Agents and Chemotherapy 64, no. 5 (February 18, 2020). http://dx.doi.org/10.1128/aac.02233-19.

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ABSTRACT Balamuthia mandrillaris is an under-reported, pathogenic free-living amoeba that causes Balamuthia amoebic encephalitis (BAE) and cutaneous skin infections. Although cutaneous infections are not typically lethal, BAE with or without cutaneous involvement is usually fatal. This is due to the lack of drugs that are both efficacious and can cross the blood-brain barrier. We aimed to discover new leads for drug discovery by screening the open-source Medicines for Malaria Venture (MMV) Malaria Box and MMV Pathogen Box, with 800 compounds total. From an initial single point screen at 1 and 10 μM, we identified 54 hits that significantly inhibited the growth of B. mandrillaris in vitro. Hits were reconfirmed in quantitative dose-response assays and 23 compounds (42.6%) were confirmed with activity greater than miltefosine, the current standard of care.

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Vallières, Cindy, and Simon V. Avery. "The Candidate Antimalarial Drug MMV665909 Causes Oxygen-Dependent mRNA Mistranslation and Synergizes with Quinoline-Derived Antimalarials." Antimicrobial Agents and Chemotherapy 61, no. 9 (June 26, 2017). http://dx.doi.org/10.1128/aac.00459-17.

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ABSTRACT To cope with growing resistance to current antimalarials, new drugs with novel modes of action are urgently needed. Molecules targeting protein synthesis appear to be promising candidates. We identified a compound (MMV665909) from the Medicines for Malaria Venture (MMV) Malaria Box of candidate antimalarials that could produce synergistic growth inhibition with the aminoglycoside antibiotic paromomycin, suggesting a possible action of the compound in mRNA mistranslation. This mechanism of action was substantiated with a Saccharomyces cerevisiae model using available reporters of mistranslation and other genetic tools. Mistranslation induced by MMV665909 was oxygen dependent, suggesting a role for reactive oxygen species (ROS). Overexpression of Rli1 (a ROS-sensitive, conserved FeS protein essential in mRNA translation) rescued inhibition by MMV665909, consistent with the drug's action on translation fidelity being mediated through Rli1. The MMV drug also synergized with major quinoline-derived antimalarials which can perturb amino acid availability or promote ROS stress: chloroquine, amodiaquine, and primaquine. The data collectively suggest translation fidelity as a novel target of antimalarial action and support MMV665909 as a promising drug candidate.

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Kraft, Thomas E., Monique R. Heitmeier, Marina Putanko, Rachel L. Edwards, Ma Xenia G. Ilagan, Maria A. Payne, Joseph M. Autry, David D. Thomas, Audrey R. Odom, and Paul W. Hruz. "A novel FRET-based screen in high-throughput format to identify inhibitors of malarial and human glucose transporters." Antimicrobial Agents and Chemotherapy, October 10, 2016, AAC.00218–16. http://dx.doi.org/10.1128/aac.00218-16.

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The glucose transporter PfHT is essential to the survival of the malaria parasitePlasmodium falciparumand has been shown to be a druggable target with high potential for pharmacological intervention. Identification of compounds against novel drug targets is crucial to combating resistance against current therapeutics. Here, we describe the development of a cell-based assay system readily adaptable to high-throughput screening that directly measures compound effects on PfHT-mediated glucose transport. Intracellular glucose concentrations are detected using a genetically encoded fluorescence resonance energy transfer (FRET)-based glucose-sensor. This allows assessment of the ability of small molecules to inhibit glucose uptake with high accuracy (Z'-factor of >0.8), thereby eliminating the need for radiolabeled substrates. Furthermore, we have adapted this assay to counter screen PfHT hits against the human orthologues GLUT1, 2, 3 and 4. We report the identification of several hits after screening the Medicines for Malaria Venture (MMV) Malaria Box, a library of 400 compounds known to inhibit erythrocytic development ofP. falciparum. Hit compounds were characterized by determining the half-maximal inhibitory concentration (IC50) for the uptake of radiolabeled glucose into isolatedP. falciparumparasites. One of our hits, compound MMV009085, shows high potency and ortholog selectivity, thereby successfully validating our assay for anti-malarial screening.

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Tadele, Markos, Solomon M. Abay, Peter Asaga, Eyasu Makonnen, and Asrat Hailu. "In vitro growth inhibitory activity of Medicines for Malaria Venture pathogen box compounds against Leishmania aethiopica." BMC Pharmacology and Toxicology 22, no. 1 (November 16, 2021). http://dx.doi.org/10.1186/s40360-021-00538-2.

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Abstract Introduction Leishmania aethiopica (L. aethiopica) is responsible for different forms of cutaneous leishmaniasis (CL) in Ethiopia. Treatment heavily depends on limited drugs, together with drawbacks like toxicity and microbial resistance. The current research aimed to investigate in vitro growth inhibitory activity of Medicines for Malaria Ventures - Pathogen Box (MMV - PB) compounds against L. aethiopica clinical isolate. Methodology Four hundred MMV – PB compounds were screened against L. aethiopica using resazurin based colourimetric assay. Compounds with > 70% inhibition were further tested using macrophage based intracellular amastigote assay. Cytotoxic and hemolytic activity of candidate hits were assessed on THP1- cells and sheep red blood cells (RBCs), respectively. In vitro drug interaction study was also conducted for the most potent hit using the combination index method. Results At the test concentration of 1 μM, twenty-three compounds showed > 50% inhibition of promastigotes parasite growth, of which 11 compounds showed > 70% inhibition. The 50% growth inhibition (IC50) of the 11 compounds was ranged from 0.024 to 0.483 μM in anti-promastigote assay and from 0.064 to 0.899 μM in intracellular amastigote assay. Candidate compounds demonstrated good safety on sheep RBCs and THP-1 cell lines. MMV688415 demonstrated a slight hemolytic activity on sheep RBC (5.3% at 25 μM) and THP-1 cell line (CC20 = 25 μM) while MMV690102 inhibited half of THP-1 cells at 36.5 μM (selectivity index = 478). No synergistic activity was observed from the combinations of MMV690102 and amphotericin B (CI > 1), and MMV690102 and Pentamidine (CI > 1) at lower and higher combination points. Conclusion The present study identified a panel of compounds that can be used as a novel starting point for lead optimization. MMV690102 appears to be the most potent inhibitor against L. aethiopica promastigotes and amastigotes. Future works should investigate the antileishmanial mechanism of action and in vivo antileishmanial activities of identified hits.

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Reader, Janette, Mariëtte E. van der Watt, Dale Taylor, Claire Le Manach, Nimisha Mittal, Sabine Ottilie, Anjo Theron, et al. "Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box." Nature Communications 12, no. 1 (January 11, 2021). http://dx.doi.org/10.1038/s41467-020-20629-8.

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AbstractChemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.

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Ullah, Imran, Raman Sharma, Antonio Mete, Giancarlo A. Biagini, Dawn M. Wetzel, and Paul D. Horrocks. "The relative rate of kill of the MMV Malaria Box compounds provides links to the mode of antimalarial action and highlights scaffolds of medicinal chemistry interest." Journal of Antimicrobial Chemotherapy, October 29, 2019. http://dx.doi.org/10.1093/jac/dkz443.

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Abstract Objectives Rapid rate-of-kill (RoK) is a key parameter in the target candidate profile 1 (TCP1) for the next-generation antimalarial drugs for uncomplicated malaria, termed Single Encounter Radical Cure and Prophylaxis (SERCaP). TCP1 aims to rapidly eliminate the initial parasite burden, ideally as fast as artesunate, but minimally as fast as chloroquine. Here we explore whether the relative RoK of the Medicine for Malaria Venture (MMV) Malaria Box compounds is linked to their mode of action (MoA) and identify scaffolds of medicinal chemistry interest. Methods We used a bioluminescence relative RoK (BRRoK) assay over 6 and 48 h, with exposure to equipotent IC50 concentrations, to compare the cytocidal effects of Malaria Box compounds with those of benchmark antimalarials. Results BRRoK assay data demonstrate the following relative RoKs, from fast to slow: inhibitors of PfATP4 > parasite haemoglobin catabolism > dihydrofolate reductase-thymidylate synthase (DHFR-TS) > dihydroorotate dehydrogenase (DHODH) > bc1 complex. Core-scaffold clustering analyses revealed intrinsic rapid cytocidal action for diamino-glycerols and 2-(aminomethyl)phenol, but slow action for 2-phenylbenz-imidazoles, 8-hydroxyquinolines and triazolopyrimidines. Conclusions This study provides proof of principle that a compound’s RoK is related to its MoA and that the target’s intrinsic RoK is also modified by factors affecting a drug’s access to it. Our findings highlight that as we use medicinal chemistry to improve potency, we can also improve the RoK for some scaffolds. Our BRRoK assay provides the necessary throughput for drug discovery and a critical decision-making tool to support development campaigns. Finally, two scaffolds, diamino-glycerols and 2-phenylbenzimidazoles, exhibit fast cytocidal action, inviting medicinal chemistry improvements towards TCP1 candidates.

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Debbert, Stefan L., Mikaela J. Hintz, Christian J. Bell, Kenya R. Earl, Grant E. Forsythe, Cécile Häberli, and Jennifer Keiser. "Activities of Quinoxaline, Nitroquinoxaline and [1,2,4]Triazolo[4,3-a]quinoxaline Analogs of MMV007204 against Schistosoma mansoni." Antimicrobial Agents and Chemotherapy, November 30, 2020. http://dx.doi.org/10.1128/aac.01370-20.

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The reliance on one drug, praziquantel, to treat the parasitic disease schistosomiasis in millions of people a year shows the need to further develop a pipeline of new drugs to treat this disease. Recently, an antimalarial quinoxaline derivative (MMV007204) from the Medicines for Malaria Venture (MMV) Malaria Box demonstrated promise against Schistosoma mansoni. In this study, 47 synthesized compounds containing quinoxaline moieties were first assayed against the larval stage of this parasite, newly transformed schistosomula (NTS); of these, 16 killed over 70% NTS at 10 μM. Further testing against NTS and adult S. mansoni yielded three compounds with 50% inhibitory concentrations (IC50s) of ≤ 0.31 μM against adult S. mansoni and selectivity indices of ≥ 8.9. Administration of these compounds as a single oral dose of 400 mg/kg of body weight to S. mansoni-infected mice yielded only moderate worm burden reduction (WBR) (9.3% – 46.3%). The discrepancy between these compounds’ good in vitro activities and their poor in vivo activities indicates that optimization of their pharmacokinetic properties may yield compounds with greater bioavailabilities and better antischistosomiasis activities in vivo.

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Vila, Taissa, and Jose L. Lopez-Ribot. "Screening the Pathogen Box for Identification of Candida albicans Biofilm Inhibitors." Antimicrobial Agents and Chemotherapy 61, no. 1 (October 24, 2016). http://dx.doi.org/10.1128/aac.02006-16.

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ABSTRACT Candida albicans remains the main causative agent of candidiasis, one of the most frequent nosocomial infections, with unacceptably high mortality rates. Biofilm formation is a major risk factor for invasive candidiasis, as Candida biofilms display high-level resistance to most antifungal agents. In this work we have screened the Pathogen Box chemical library (Medicines for Malaria Venture [MMV], Switzerland) in search for inhibitors of C. albicans biofilm formation. Our initial screen identified seven hits, and additional dose-response assays confirmed the biofilm-inhibitory activity of six of these small molecules. Three compounds, MMV688768, MMV687273, and MMV687807, were also able to reduce the metabolic activity of cells within preformed biofilms. Interestingly, the most potent of these, compound MMV688768, displayed increased antibiofilm activity compared to its activity against planktonic cultures, indicating that it may affect processes with a predominant role during the biofilm mode of growth. This compound demonstrated a high selectivity index when its antibiofilm activity was compared with its toxicity in liver hepatocellular cells. In vitro combination assays showed a synergistic interaction between compound MMV688768 and fluconazole against preformed biofilms. Overall, our results indicate that this compound may constitute a potential candidate for further clinical development.

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Tong, Jie Xin, Rajesh Chandramohanadas, and Kevin Shyong-Wei Tan. "High-Content Screening of the Medicines for Malaria Venture Pathogen Box forPlasmodium falciparumDigestive Vacuole-Disrupting Molecules Reveals Valuable Starting Points for Drug Discovery." Antimicrobial Agents and Chemotherapy 62, no. 3 (January 8, 2018). http://dx.doi.org/10.1128/aac.02031-17.

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ABSTRACTPlasmodium falciparuminfections leading to malaria have severe clinical manifestations and high mortality rates. Chloroquine (CQ), a former mainstay of malaria chemotherapy, has been rendered ineffective due to the emergence of widespread resistance. Recent studies, however, have unveiled a novel mode of action in which low-micromolar levels of CQ permeabilized the parasite's digestive vacuole (DV) membrane, leading to calcium efflux, mitochondrial depolarization, and DNA degradation. These phenotypes implicate the DV as an alternative target of CQ and suggest that DV disruption is an attractive target for exploitation by DV-disruptive antimalarials. In the current study, high-content screening of the Medicines for Malaria Venture (MMV) Pathogen Box (2015) was performed to select compounds which disrupt the DV membrane, as measured by the leakage of intravacuolar Ca2+using the calcium probe Fluo-4 AM. The hits were further characterized by hemozoin biocrystallization inhibition assays and dose-response half-maximal (50%) inhibitory concentration (IC50) assays across resistant and sensitive strains. Three hits, MMV676380, MMV085071, and MMV687812, were shown to demonstrate a lack of CQ cross-resistance in parasite strains and field isolates. Through systematic analyses, MMV085071 emerged as the top hit due to its rapid parasiticidal effect, low-nanomolar IC50, and good efficacy in triggering DV disruption, mitochondrial degradation, and DNA fragmentation inP. falciparum. These programmed cell death (PCD)-like phenotypes following permeabilization of the DV suggests that these compounds kill the parasite by a PCD-like mechanism. From the drug development perspective, MMV085071, which was identified to be a potent DV disruptor, offers a promising starting point for subsequent hit-to-lead generation and optimization through structure-activity relationships.

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Ahyong, Vida, Christine M. Sheridan, Kristoffer E. Leon, Jessica N. Witchley, Jonathan Diep, and Joseph L. DeRisi. "Identification of Plasmodium falciparum specific translation inhibitors from the MMV Malaria Box using a high throughput in vitro translation screen." Malaria Journal 15, no. 1 (March 17, 2016). http://dx.doi.org/10.1186/s12936-016-1231-8.

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Spalenka, Jérémy, Sandie Escotte-Binet, Ali Bakiri, Jane Hubert, Jean-Hugues Renault, Frédéric Velard, Simon Duchateau, Dominique Aubert, Antoine Huguenin, and Isabelle Villena. "Discovery of New Inhibitors of Toxoplasma gondii via the Pathogen Box." Antimicrobial Agents and Chemotherapy 62, no. 2 (November 13, 2017). http://dx.doi.org/10.1128/aac.01640-17.

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ABSTRACT Toxoplasma gondii is a cosmopolitan protozoan parasite which affects approximately 30% of the population worldwide. The drugs currently used against toxoplasmosis are few in number and show several limitations, such as drug intolerance, poor bioavailability, or drug resistance mechanism developed by the parasite. Thus, it is important to find new compounds able to inhibit parasite invasion or proliferation. In this study, the 400 compounds of the open-access Pathogen Box, provided by the Medicines for Malaria Venture (MMV) foundation, were screened for their anti-Toxoplasma gondii activity. A preliminary in vitro screening performed over 72 h by an enzyme-linked immunosorbent assay (ELISA) revealed 15 interesting compounds that were effective against T. gondii at 1 μM. Their cytotoxicity was estimated on Vero cells, and their 50% inhibitory concentrations (IC50) were further calculated. As a result, eight anti-Toxoplasma gondii compounds with an IC50 of less than 2 μM and a selectivity index (SI) value of greater than 4 were identified. The most active was MMV675968, showing an IC50 of 0.02 μM and a selectivity index value equal to 275. Two other compounds, MMV689480 and MMV687807, also showed a good activity against T. gondii, with IC50s of 0.10 μM (SI of 86.6) and 0.15 μM (SI of 11.3), respectively. Structure-activity relationships for the eight selected compounds also were discussed on the basis of fingerprinting similarity measurements using the Tanimoto method. The anti-Toxoplasma gondii compounds highlighted here represent potential candidates for the development of new drugs that could be used against toxoplasmosis.

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Maccesi, Martina, Pedro H. N. Aguiar, Valérian Pasche, Melody Padilla, Brian M. Suzuki, Sandro Montefusco, Ruben Abagyan, Jennifer Keiser, Marina M. Mourão, and Conor R. Caffrey. "Multi-center screening of the Pathogen Box collection for schistosomiasis drug discovery." Parasites & Vectors 12, no. 1 (October 22, 2019). http://dx.doi.org/10.1186/s13071-019-3747-6.

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Abstract Background Over the past five years, as a public service to encourage and accelerate drug discovery for diseases of poverty, the Medicines for Malaria Venture (MMV) has released box sets of 400 compounds named the Malaria, Pathogen and Stasis Boxes. Here, we screened the Pathogen Box against the post-infective larvae (schistosomula) of Schistosoma mansoni using assays particular to the three contributing institutions, namely, the University of California San Diego (UCSD) in the USA, the Swiss Tropical and Public Health Institute (Swiss TPH) in Switzerland, and the Fundação Oswaldo Cruz (FIOCRUZ) in Brazil. With the same set of compounds, the goal was to determine the degree of inter-assay variability and identify a core set of active compounds common to all three assays. New drugs for schistosomiasis would be welcome given that current treatment and control strategies rely on chemotherapy with just one drug, praziquantel. Methods Both the UCSD and Swiss TPH assays utilize daily observational scoring methodologies over 72 h, whereas the FIOCRUZ assay employs XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) at 72 h to measure viability as a function of NAD+/NADH redox state. Raw and transformed data arising from each assay were assembled for comparative analysis. Results For the UCSD and Swiss TPH assays, there was strong concordance of at least 87% in identifying active and inactive compounds on one or more of the three days. When all three assays were compared at 72 h, concordance remained a robust 74%. Further, robust Pearsonʼs correlations (0.48–0.68) were measured between the assays. Of those actives at 72 h, the UCSD, Swiss TPH and FIOCRUZ assays identified 86, 103 and 66 compounds, respectively, of which 35 were common. Assay idiosyncrasies included the identification of unique compounds, the differential ability to identify known antischistosomal compounds and the concept that compounds of interest might include those that increase metabolic activity above baseline. Conclusions The inter-assay data generated were in good agreement, including with previously reported data. A common set of antischistosomal molecules for further exploration has been identified.

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Nick, Marina, Frederick A. Partridge, Ruth Forman, Carole J. R. Bataille, Kathryn J. Else, Angela J. Russell, and David B. Sattelle. "Screening the Medicines for Malaria Venture (MMV) Pandemic Response Box chemical library on Caenorhabditis elegans identifies re-profiled candidate anthelmintic drug leads." Frontiers in Tropical Diseases 3 (October 13, 2022). http://dx.doi.org/10.3389/fitd.2022.1017900.

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The 3 major classes of soil transmitted helminths (whipworm, hookworm and Ascaris) affect 1.5 billion people worldwide mostly in poor countries, where they have adverse effects on child development, nutrition, and the work capacity of adults. Although there are drugs effective on Ascaris, notably the benzimidazoles, those same drugs show poor efficacy particularly against whipworm (Trichuris trichiura) and to a certain extent hookworm. Parasitic nematodes also infect farm livestock and companion animals. Resistance to currently deployed human and veterinary anthelmintic drugs is a growing problem. Therefore, new chemical anthelmintic lead compounds are urgently needed. One of the fastest routes to a novel therapeutic lead is to screen libraries of drugs which are either already approved for human use or have already been part of clinical trials. We have pursued this approach to anthelmintic lead discovery using an invertebrate automated phenotyping platform (INVAPP) for screening chemicals and the well-established nematode genetic model organism Caenorhabditis elegans. The 400 compound Medicines for Malaria Venture (MMV) Pandemic Response Box library was screened with each compound tested initially at 1.0x10-4 M. We identified 6 compounds (MMV1593515 (vorapaxar), MMV102270 (diphyllin), MMV1581032 (ABX464), MMV1580796 (rubitecan), MMV1580505 and MMV1593531) active in both an L1-L4 growth/motility assay and in an L4 motility assay. For vorapaxar, an EC50 of 5.7x10-7 M was observed, a value comparable to those of some commercial anthelmintics. Although not a parasite, the ease with which high-throughput screens can be pursued on the free-living nematode C. elegans makes this a useful approach to identify chemical leads and complements the often lower-throughput experiments on parasitic nematode models.

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Villares, Marie, Nelly Lourenço, Jeremy Berthelet, Suzanne Lamotte, Leslie Regad, Souhila Medjkane, Eric Prina, Fernando Rodrigues-Lima, Gerald F. Späth, and Jonathan B. Weitzman. "Trifloxystrobin blocks the growth of Theileria parasites and is a promising drug to treat Buparvaquone resistance." Communications Biology 5, no. 1 (November 15, 2022). http://dx.doi.org/10.1038/s42003-022-03981-x.

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AbstractTheileria parasites are responsible for devastating cattle diseases, causing major economic losses across Africa and Asia. Theileria spp. stand apart from other apicomplexa parasites by their ability to transform host leukocytes into immortalized, hyperproliferating, invasive cells that rapidly kill infected animals. The emergence of resistance to the theilericidal drug Buparvaquone raises the need for new anti-Theileria drugs. We developed a microscopy-based screen to reposition drugs from the open-access Medicines for Malaria Venture (MMV) Pathogen Box. We show that Trifloxystrobin (MMV688754) selectively kills lymphocytes or macrophages infected with Theileria annulata or Theileria parva parasites. Trifloxystrobin treatment reduced parasite load in vitro as effectively as Buparvaquone, with similar effects on host gene expression, cell proliferation and cell cycle. Trifloxystrobin also inhibited parasite differentiation to merozoites (merogony). Trifloxystrobin inhibition of parasite survival is independent of the parasite TaPin1 prolyl isomerase pathway. Furthermore, modeling studies predicted that Trifloxystrobin and Buparvaquone could interact distinctly with parasite Cytochrome B and we show that Trifloxystrobin was still effective against Buparvaquone-resistant cells harboring TaCytB mutations. Our study suggests that Trifloxystrobin could provide an effective alternative to Buparvaquone treatment and represents a promising candidate for future drug development against Theileria spp.

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Coimbra, Laís D., Alexandre Borin, Marina Fontoura, Humberto D. Gravina, Alice Nagai, Jacqueline Farinha Shimizu, Karina Bispo-dos-Santos, et al. "Identification of Compounds With Antiviral Activity Against SARS-CoV-2 in the MMV Pathogen Box Using a Phenotypic High-Throughput Screening Assay." Frontiers in Virology 2 (April 14, 2022). http://dx.doi.org/10.3389/fviro.2022.854363.

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Until December 2021, the COVID-19 pandemic has caused more than 5.5 million deaths. Vaccines are being deployed worldwide to mitigate severe disease and death, but continued transmission and the emergence of SARS-CoV-2 variants indicate that specific treatments against COVID-19 are still necessary. We screened 400 compounds from the Medicines for Malaria Venture (MMV) Pathogen Box seeking for molecules with antiviral activity against SARS-CoV-2 by using a high-throughput screening (HTS) infection assay in Vero CCL81 cells. On resupply of 15 selected hit compounds, we confirmed that 7 of them presented a dose-dependent cytoprotective activity against SARS-CoV-2-induced cytopathic effect (CPE) in the micromolar range. They were validated in low-throughput infection assays using four different cell lines, including the human lung Calu-3 cell line. MMV000063, MMV024937, MMV688279, and MMV688991 reduced viral load in cell culture, assessed by RT-qPCR and viral plaque assay, while MMV688279 and MMV688991 (also known as nitazoxanide) were the most promising, reducing SARS-CoV-2 load by at least 100-fold at 20 µM in almost all cell types tested. Our results indicate that active anti-SARS-CoV-2 molecules exist within the repertoire of antiviral, antiparasitic and antimicrobial compounds available to date. Although the mode of action by which MMV688279 and MMV688991 reduce SARS-CoV-2 replication is yet unknown, the fact that they were active in different cell types holds promise not only for the discovery of new therapeutic targets, but also for the development of novel antiviral medicines against COVID-19.

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