Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1.

Dans, MG; Boulet, CORCID logo; Watson, GM; Nguyen, W; Dziekan, JM; Evelyn, CORCID logo; Reaksudsan, K; Mehra, S; Razook, Z; Geoghegan, NDORCID logo; +21 more...Mlodzianoski, MJORCID logo; Goodman, CD; Ling, DBORCID logo; Jonsdottir, TKORCID logo; Tong, J; Famodimu, MT; Kristan, MORCID logo; Pollard, H; Stewart, LB; Brandner-Garrod, L; Sutherland, CJORCID logo; Delves, MJORCID logo; McFadden, GI; Barry, AEORCID logo; Crabb, BS; de Koning-Ward, TFORCID logo; Rogers, KLORCID logo; Cowman, AFORCID logo; Tham, WORCID logo; Sleebs, BEORCID logo; Gilson, PRORCID logo and (2024) Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1. Nature communications, 15 (1). 5219-. ISSN 2041-1723 DOI: 10.1038/s41467-024-49491-8
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With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite's lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.


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