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

Nat Commun. 2024 Jun 18;15(1):5219. doi: 10.1038/s41467-024-49491-8.

Madeline G Dans ^# ¹ ² ³ ⁴, Coralie Boulet ^# ⁵ ⁶, Gabrielle M Watson ⁷ ⁸, William Nguyen ⁷ ⁸, Jerzy M Dziekan ⁷ ⁸, Cindy Evelyn ⁷ ⁸, Kitsanapong Reaksudsan ⁷ ⁸, Somya Mehra ⁵ ⁹, Zahra Razook ⁵ ⁹, Niall D Geoghegan ⁷ ⁸, Michael J Mlodzianoski ⁷ ⁸, Christopher Dean Goodman ¹⁰, Dawson B Ling ⁵, Thorey K Jonsdottir ⁵ ¹¹ ¹² ¹³, Joshua Tong ⁷, Mufuliat Toyin Famodimu ¹⁴, Mojca Kristan ¹⁵, Harry Pollard ¹⁵, Lindsay B Stewart ¹⁵, Luke Brandner-Garrod ¹⁵, Colin J Sutherland ¹⁴ ¹⁵, Michael J Delves ¹⁴, Geoffrey I McFadden ¹⁰, Alyssa E Barry ⁵ ⁹, Brendan S Crabb ⁵ ¹¹ ¹⁶, Tania F de Koning-Ward ⁹, Kelly L Rogers ⁷ ⁸, Alan F Cowman ⁷ ⁸, Wai-Hong Tham ⁷ ⁸, Brad E Sleebs ⁷ ⁸, Paul R Gilson ¹⁷ ¹⁸

Affiliations

1 Burnet Institute, Melbourne, VIC, 3004, Australia. dans.m@wehi.edu.au.
2 Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia. dans.m@wehi.edu.au.
3 Institute of Mental and Physical Health and Clinical Translation (IMPACT) and School of Medicine, Deakin University, Geelong, VIC, 3220, Australia. dans.m@wehi.edu.au.
4 Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia. dans.m@wehi.edu.au.
5 Burnet Institute, Melbourne, VIC, 3004, Australia.
6 Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, 1206, Switzerland.
7 Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia.
8 Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia.
9 Institute of Mental and Physical Health and Clinical Translation (IMPACT) and School of Medicine, Deakin University, Geelong, VIC, 3220, Australia.
10 School of Biosciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
11 Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC, 3010, Australia.
12 Department of Molecular Biology, Umeå University, Umeå, 901 87, Sweden.
13 The Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå, Sweden.
14 Department of Infection Biology, Faculty of Infectious Diseases, London School of Hygiene and Tropical Medicine, WC1E 7HT, London, UK.
15 Wellcome Trust Human Malaria Transmission Facility, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK.
16 Monash University, 3800, Melbourne, VIC, Australia.
17 Burnet Institute, Melbourne, VIC, 3004, Australia. paul.gilson@burnet.edu.au.
18 Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC, 3010, Australia. paul.gilson@burnet.edu.au.
# Contributed equally.

PMID: 38890312 DOI: 10.1038/s41467-024-49491-8

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-161801

MMV006833

Antimalarial Agent

Parasite

Infection

Name
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