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

Madeline G. Dans (), Coralie Boulet, Gabrielle M. Watson, William Nguyen, Jerzy M. Dziekan, Cindy Evelyn, Kitsanapong Reaksudsan, Somya Mehra, Zahra Razook, Niall D. Geoghegan, Michael J. Mlodzianoski, Christopher Dean Goodman, Dawson B. Ling, Thorey K. Jonsdottir, Joshua Tong, Mufuliat Toyin 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. Koning-Ward, Kelly L. Rogers, Alan F. Cowman, Wai-Hong Tham, Brad E. Sleebs and Paul R. Gilson ()
Additional contact information
Madeline G. Dans: Burnet Institute
Coralie Boulet: Burnet Institute
Gabrielle M. Watson: Walter and Eliza Hall Institute
William Nguyen: Walter and Eliza Hall Institute
Jerzy M. Dziekan: Walter and Eliza Hall Institute
Cindy Evelyn: Walter and Eliza Hall Institute
Kitsanapong Reaksudsan: Walter and Eliza Hall Institute
Somya Mehra: Burnet Institute
Zahra Razook: Burnet Institute
Niall D. Geoghegan: Walter and Eliza Hall Institute
Michael J. Mlodzianoski: Walter and Eliza Hall Institute
Christopher Dean Goodman: The University of Melbourne
Dawson B. Ling: Burnet Institute
Thorey K. Jonsdottir: Burnet Institute
Joshua Tong: Walter and Eliza Hall Institute
Mufuliat Toyin Famodimu: London School of Hygiene and Tropical Medicine
Mojca Kristan: London School of Hygiene & Tropical Medicine
Harry Pollard: London School of Hygiene & Tropical Medicine
Lindsay B. Stewart: London School of Hygiene & Tropical Medicine
Luke Brandner-Garrod: London School of Hygiene & Tropical Medicine
Colin J. Sutherland: London School of Hygiene and Tropical Medicine
Michael J. Delves: London School of Hygiene and Tropical Medicine
Geoffrey I. McFadden: The University of Melbourne
Alyssa E. Barry: Burnet Institute
Brendan S. Crabb: Burnet Institute
Tania F. Koning-Ward: Deakin University
Kelly L. Rogers: Walter and Eliza Hall Institute
Alan F. Cowman: Walter and Eliza Hall Institute
Wai-Hong Tham: Walter and Eliza Hall Institute
Brad E. Sleebs: Walter and Eliza Hall Institute
Paul R. Gilson: Burnet Institute

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49491-8

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