Nature Communications (Jun 2024)
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. de Koning-Ward,
- Kelly L. Rogers,
- Alan F. Cowman,
- Wai-Hong Tham,
- Brad E. Sleebs,
- Paul R. Gilson
Affiliations
- 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
- School of Biosciences, The University of Melbourne
- Dawson B. Ling
- Burnet Institute
- Thorey K. Jonsdottir
- Burnet Institute
- Joshua Tong
- Walter and Eliza Hall Institute
- Mufuliat Toyin Famodimu
- Department of Infection Biology, Faculty of Infectious Diseases, London School of Hygiene and Tropical Medicine
- Mojca Kristan
- Wellcome Trust Human Malaria Transmission Facility, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine
- Harry Pollard
- Wellcome Trust Human Malaria Transmission Facility, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine
- Lindsay B. Stewart
- Wellcome Trust Human Malaria Transmission Facility, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine
- Luke Brandner-Garrod
- Wellcome Trust Human Malaria Transmission Facility, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine
- Colin J. Sutherland
- Department of Infection Biology, Faculty of Infectious Diseases, London School of Hygiene and Tropical Medicine
- Michael J. Delves
- Department of Infection Biology, Faculty of Infectious Diseases, London School of Hygiene and Tropical Medicine
- Geoffrey I. McFadden
- School of Biosciences, The University of Melbourne
- Alyssa E. Barry
- Burnet Institute
- Brendan S. Crabb
- Burnet Institute
- Tania F. de Koning-Ward
- Institute of Mental and Physical Health and Clinical Translation (IMPACT) and School of Medicine, 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
- DOI
- https://doi.org/10.1038/s41467-024-49491-8
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
