Aryl amino acetamides prevent the development ofPlasmodium falciparumrings via inhibition of the lipid transfer protein PfSTART1
Author:
Dans Madeline G., Boulet Coralie, Watson Gabrielle M., Nguyen William, Dziekan Jerzy M., Evelyn Cindy, Reaksudsan Kitsanapong, Mehra Somya, Razook Zahra, Geoghegan Niall D., Mlodzianoski Michael J., Goodman Christopher Dean, Ling Dawson B., Jonsdottir Thorey K., Tong Joshua, Famodimu Mufuliat Toyin, Kouskousis Betty, Delves Michael J., McFadden Geoffrey I., Barry Alyssa E.ORCID, Crabb Brendan S., de Koning-Ward Tania F., Rogers Kelly L.ORCID, Cowman Alan F., Tham Wai-HongORCID, Sleebs Brad E., Gilson Paul R.
Abstract
AbstractWith resistance to most antimalarials increasing, it is imperative that new antimalarial drugs are developed to replace or complement front-line artemisinin therapies. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited ring development of newly invaded merozoites. Here, we selected parasites resistant to M-833 and identified independent mutations arising in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introduction of the identified PfSTART1 mutations into wildtype parasites reproduced resistance to both M-833 and highly potent analogues, confirming PfSTART1 mutations were sufficient to confer resistance. The analogues bound to recombinant PfSTART1 with nanomolar affinity. We also demonstrated selective PfSTART1 engagement by the analogues using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assay for the first time inPlasmodium.Imaging of newly invaded merozoites showed the inhibitors prevented the conversion into larger amoeboid ring-stage parasites potentially through the inhibition of phospholipid transfer from the parasite to the encasing parasitophorous vacuole membrane (PVM) and/or within the parasite. We show that these PfSTART1 inhibitors also block transmission. With multiple stages of the parasite’s lifecycle being targeted by PfSTART1 inhibitors, this protein therefore represents a novel drug target with a new mechanism of action.
Publisher
Cold Spring Harbor Laboratory
Reference92 articles.
1. Identification of small-molecule inhibitors of the steroidogenic acute regulatory protein (STARD1) by structure-based design;Bioorg Med Chem Lett,2012 2. Asif, K. , Memeo, L. , Palazzolo, S. , Frión-Herrera, Y. , Parisi, S. , Caligiuri, I. , Canzonieri, V. , Granchi, C. , Tuccinardi, T. , and Rizzolio, F . (2021). STARD3: A Prospective Target for Cancer Therapy. In Cancers. 3. Plasmodium falciparum Transfected with Ultra Bright NanoLuc Luciferase Offers High Sensitivity Detection for the Screening of Growth and Cellular Trafficking Inhibitors 4. Plasmodium falciparum: Differential Sensitivity In Vitro to E-64 (Cysteine Protease Inhibitor) and Pepstatin A (Aspartyl Protease Inhibitor) 5. Barnes, C.B.G. , Dans, M.G. , Jonsdottir, T.K. , Crabb, B.S. , and Gilson, P.R . (2022). PfATP4 inhibitors in the Medicines for Malaria Venture Malaria Box and Pathogen Box block the schizont-to-ring transition by inhibiting egress rather than invasion. Frontiers in Cellular and Infection Microbiology 12.
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