Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box.

  • Journal Article
  • Research Support, Non-U.S. Gov't
Journal:
Nature communications, Volume: 12, Issue: 1
Published:
January 11, 2021
PMID:
33431834
Authors:
Janette Reader J, Mariëtte E van der Watt ME, Dale Taylor D, Claire Le Manach C, Nimisha Mittal N, Sabine Ottilie S, Anjo Theron A, Phanankosi Moyo P, Erica Erlank E, Luisa Nardini L, Nelius Venter N, Sonja Lauterbach S, Belinda Bezuidenhout B, Andre Horatscheck A, Ashleigh van Heerden A, Natalie J Spillman NJ, Anne N Cowell AN, Jessica Connacher J, Daniel Opperman D, Lindsey M Orchard LM, Manuel Llinás M, Eva S Istvan ES, Daniel E Goldberg DE, Grant A Boyle GA, David Calvo D, Dalu Mancama D, Theresa L Coetzer TL, Elizabeth A Winzeler EA, James Duffy J, Lizette L Koekemoer LL, Gregory Basarab G, Kelly Chibale K, Lyn-Marié Birkholtz LM
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Abstract:

Chemical 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.

Courtesy of the U.S. National Library of Medicine