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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; Kristan, Mojca; Pollard, Harry; Stewart, Lindsay B.; Brandner-Garrod, Luke; Sutherland, Colin J.; Delves, Michael J.; McFadden, Geoffrey I.; Barry, Alyssa E.; [...]

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

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  • Media type: E-Article
  • Title: Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1
  • Contributor: 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; Kristan, Mojca; Pollard, Harry; Stewart, Lindsay B.; Brandner-Garrod, Luke; Sutherland, Colin J.; Delves, Michael J.; McFadden, Geoffrey I.; Barry, Alyssa E.; [...]
  • Published: Springer Science and Business Media LLC, 2024
  • Published in: Nature Communications, 15 (2024) 1
  • Language: English
  • DOI: 10.1038/s41467-024-49491-8
  • ISSN: 2041-1723
  • Origination:
  • Footnote:
  • Description: AbstractWith 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.
  • Access State: Open Access