Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1
Madeline G. Dans, Coralie Boulet, G. M. Watson, William Nguyen, Jerzy M. Dziekan, Cindy Evelyn, Kitsanapong Reaksudsan, Somya Mehra, Zahra Razook, Niall D. Geoghegan, Michael J. Mlodzianoski, C.D. Goodman, Dawson B. Ling, Thorey K. Jonsdottir, Joshua Tong, Mufuliat T. Famodimu, Mojca Kristan, Harry Pollard, Lindsay B. Stewart, Luke Brandner-Garrod, Colin J. Sutherland, Michael J. Delves, Geoffrey I. McFadden, Alyssa E. Barry, Brendan S. Crabb, Tania F. de Koning‐Ward, Kelly L. Rogers, Alan F. Cowman, Wai‐Hong Tham, Brad E. Sleebs, Paul R. Gilson
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.