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

Dans, MG; Boulet, C; Watson, GM; Nguyen, W; Dziekan, JM; Evelyn, C; Reaksudsan, K; Mehra, S; Razook, Z; Geoghegan, ND; Mlodzianoski, MJ; Goodman, CD; Ling, DB; Jonsdottir, TK; Tong, J; Famodimu, MT; Kristan, M; Pollard, H; Stewart, LB; Brandner-Garrod, L; Sutherland, CJ; Delves, MJ; McFadden, GI; Barry, AE; Crabb, BS; de Koning-Ward, TF; Rogers, KL; Cowman, AF; Tham, WH; Sleebs, BE; Gilson, PR

Author(s): Dans, MG; Boulet, C; Watson, GM; Nguyen, W; Dziekan, JM; Evelyn, C; Reaksudsan, K; Mehra, S; Razook, Z; Geoghegan, ND; Mlodzianoski, MJ; Goodman, CD; Ling, DB; Jonsdottir, TK; Tong, J; Famodimu, MT; Kristan, M; Pollard, H; Stewart, LB; Brandner-Garrod, L; Sutherland, CJ; Delves, MJ; McFadden, GI; Barry, AE; Crabb, BS; de Koning-Ward, TF; Rogers, KL; Cowman, AF; Tham, WH; Sleebs, BE; Gilson, PR;
Details: Publication Year 2024-06-18,Volume 15,Issue #1,Page 5219
Journal Title: Nature Communications
Abstract: 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.
Publisher: Springer Nature
Keywords: *Plasmodium falciparum/drug effects/genetics/metabolism/growth & development; *Acetamides/pharmacology/chemistry; *Protozoan Proteins/metabolism/genetics; *Antimalarials/pharmacology/chemistry; Animals; Carrier Proteins/metabolism/genetics; Mutation; Malaria, Falciparum/parasitology/prevention & control/drug therapy; Humans; Drug Resistance/genetics/drug effects; Life Cycle Stages/drug effects
Research Division(s): Chemical Biology; Advanced Technology And Biology; Infectious Diseases And Immune Defence; Structural Biology
Publisher's Version: https://doi.org/10.1038/s41467-024-49491-8
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-024-49491-8
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41467-024-49491-8.pdf - (2.82MB, application/pdf)

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