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Source MMV Pandemic Response Box Janette R bioRxiv preprint doi: https://doi.org/10.1101/2020.06.05.133405; this version posted June 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Multistage and transmission-blocking targeted antimalarials discovered from the open- 2 source MMV Pandemic Response Box 3 Janette Reader1a, Mariëtte E. van der Watt1a, Dale Taylor2, Claire Le Manach2, Nimisha 4 Mittal3, SaBine Ottilie3, Anjo Theron4, Phanankosi Moyo1, Erica Erlank5, Luisa Nardini5, 5 Nelius Venter5, Sonja Lauterbach6, Belinda Bezuidenhout6, Andre Horatscheck2, Ashleigh 6 van Heerden1, Grant A. Boyle2, David Calvo7, Dalu Mancama4, Theresa L. Coetzer6, 7 Elizabeth A. Winzeler3, James Duffy8, Lizette L. Koekemoer4, Gregory BasaraB2, Kelly 8 ChiBale2,9, Lyn-Marié Birkholtz1 9 1 Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria 10 Control, University of Pretoria, Hatfield, Pretoria 0028, South Africa 11 2 Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 12 7701, South Africa 13 3 Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of 14 California San Diego, La Jolla, California 92093-076, USA 15 4 Next Generation Health, Council for Scientific and Industrial Research, PO Box 395, Pretoria 16 0001, South Africa 17 5 Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, 18 University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, 19 National Institute for Communicable Diseases of the National Health Laboratory Service, 20 Johannesburg, 2193, South Africa 21 6 Department of Molecular Medicine and Hematology, Wits Research Institute for Malaria, 22 School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, 23 Johannesburg, 2193, South Africa 24 7 Global Health Incubator Unit, GlaxoSmithKline (GSK), Severo Ochoa, 2, 28760, Tres 25 Cantos, Madrid, Spain 26 8 Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, 1215, 27 Geneva, Switzerland 28 9 South African Medical Research Council, Drug Discovery and Development Research Unit, 29 Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, 30 University of Cape Town, Rondebosch 7701, South Africa 31 32 a These authors contributed equally 33 * Corresponding Author: Department of Biochemistry, Genetics and Microbiology, University 34 of Pretoria, Private Bag x20, Hatfield, Pretoria 0028, South Africa bioRxiv preprint doi: https://doi.org/10.1101/2020.06.05.133405; this version posted June 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 35 Tel.: +27 12 420 2479; Fax: +27 12 362 5302. E-mail address: [email protected] 36 37 Running title: Antimalarial profiling of the MMV Pandemic Response Box bioRxiv preprint doi: https://doi.org/10.1101/2020.06.05.133405; this version posted June 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 38 Abstract 39 40 New chemical matter is needed to target the divergent biology associated with the different 41 life cycle stages of Plasmodium. Here, we report the parallel screening of the Medicines for 42 Malaria Venture Pandemic Response Box to identify multistage-active and stage-specific 43 compounds against various life cycle stages of Plasmodium parasites (asexual parasites, 44 stage IV/V gametocytes, gametes, oocysts and liver stages) and for endectocidal activity. Hits 45 displayed unique chemotypes and included two multistage-active compounds, 16 asexual- 46 targeted, six with prophylactic potential and ten gametocyte-targeted compounds. Notably, 47 four structurally diverse gametocyte-targeted compounds with potent transmission-blocking 48 activity were identified: the JmjC inhibitor ML324, two azole antifungals including 49 eberconazole, and the antitubercular clinical candidate SQ109. Besides ML324, none of these 50 have previously attributed antiplasmodial activity, emphasizing the success of de novo parallel 51 screening against different Plasmodium stages to deliver leads with novel modes-of-action. 52 Importantly, the discovery of such transmission-blocking targeted compounds covers a 53 previously unexplored base for delivery of compounds required for malaria elimination 54 strategies. 55 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.05.133405; this version posted June 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 56 INTRODUCTION 57 Malaria treatment solely relies on drugs that target the parasite but current treatment options 58 have a finite lifespan due to resistance development. Moreover, whilst current antimalarials 59 are curative of asexual blood stage parasitemia and associated malaria symptoms, they 60 cannot all be used prophylactically and typically do not effectively block transmission. This 61 limits their utility in malaria elimination strategies, where the latter dictates that chemotypes 62 should block human-to-mosquito (gametocyte and gametes) and mosquito-to-human 63 (sporozoites and liver schizonts) transmission. 64 The transmission stages of malaria parasites are seen as parasite population 65 bottlenecks,1 with as few as 100 sporozoites able to initiate an infection after migrating to the 66 liver where exoerythrocytic schizogony occurs. The subsequent release of thousands of 67 daughter cells, which in turn infect erythrocytes, initiates the extensive population expansion 68 that occurs during asexual replication. A minor proportion (~1%)2 of the proliferating asexual 69 parasites will undergo sexual differentiation to form mature stage V gametocytes, a 10-14 day 70 process in the most virulent parasite Plasmodium falciparum. Only ~103 of these falciform- 71 shaped mature gametocytes are taken up by the next feeding mosquito to transform into male 72 and female gametes in the mosquito’s midgut.3 Fertilization results in zygote development, 73 and a motile ookinete that passes through the midgut wall forms an oocyst from which 74 sporozoites develop, making the mosquito infectious. 75 The sporozoite and gametocyte population bottlenecks have been the basis of enticing 76 arguments towards the development of chemotypes able to target them. However, most 77 compounds able to kill asexual parasites are either ineffective in preventing infection (hepatic 78 development) and blocking transmission (gametocytogenesis) or are compromised by 79 resistance development (e.g. antifolates active as prophylactics). Some compounds also have 80 toxicity concerns (e.g. primaquine targeting gametocytes with associated hemolytic toxicity in 81 glucose-6-phosphate dehydrogenase deficient patients). Patients treated with current 82 antimalarials or asymptomatic carries, may have sufficient levels of gametocytes that can be 83 transmitted to the mosquito and sustain the malaria burden. The development of gametocyte- 84 targeted transmission-blocking compounds is therefore essential for a complete strategy 85 directed at eliminating malaria. 86 Phenotypic screenings of millions of compounds have successfully identified new 87 antimalarial hits to populate the drug discovery pipeline. However, the majority of these 88 screens assessed activity against asexual blood stage parasites as the primary filter, and hits 89 were only profiled thereafter for activity against additional life cycle stages. Whilst this strategy 90 can identify compounds targeting two or more life cycle stages, it does not allow de novo 91 discovery of compounds with selective activity against specific life cycle stages such as 92 gametocytes. Parallel screening against multiple life cycle stages would best identify such bioRxiv preprint doi: https://doi.org/10.1101/2020.06.05.133405; this version posted June 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 93 compounds. These efforts rely on selective and predictive assays for gametocytocidal 94 activity,4 transmission-blocking,5, 6 and hepatic development.7 Moreover, identifying stage- 95 specific compounds will allow the divergent cell biology associated with the different life cycle 96 states to be targeted.5, 6, 8 Recently, parallel screening of diversity sets has resulted in reports 97 of such stage-specific compounds.7, 9, 10, 11 98 The Medicines for Malaria Venture (MMV) Pandemic Response Box (PRB) (in 99 partnership with DNDi) is a collection of 400 drug-like compounds stratified by antibacterial, 100 antiviral or antifungal activity (201, 153 and 46 compounds, respectively), with some 101 compounds having antineoplastic activity. The unique and diverse nature of the compounds 102 in the box allow one to explore
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