Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 01 2021
11 01 2021
Historique:
received:
22
05
2020
accepted:
10
12
2020
entrez:
12
1
2021
pubmed:
13
1
2021
medline:
22
1
2021
Statut:
epublish
Résumé
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
Identifiants
pubmed: 33431834
doi: 10.1038/s41467-020-20629-8
pii: 10.1038/s41467-020-20629-8
pmc: PMC7801607
doi:
Substances chimiques
Antimalarials
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
269Subventions
Organisme : NIAID NIH HHS
ID : R01 AI152533
Pays : United States
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