Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design - Compartimentation et dynamique cellulaires Accéder directement au contenu
Pré-Publication, Document De Travail Année : 2022

Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design

Dihia Moussaoui
  • Fonction : Auteur
James Robblee
  • Fonction : Auteur
Daniel Auguin
  • Fonction : Auteur
Fabio Fisher
  • Fonction : Auteur
Patricia Fagnant
  • Fonction : Auteur
Jill Macfarlane
  • Fonction : Auteur
Julia Schaletzky
  • Fonction : Auteur
Eddie Wehri
  • Fonction : Auteur
Christoph Mueller-Dieckmann
  • Fonction : Auteur
Jake Baum
  • Fonction : Auteur
Kathleen Trybus
Anne Houdusse

Résumé

Abstract Malaria is responsible for more than a half million deaths per year. The Plasmodium parasites responsible continue to develop resistance to all known agents, despite treatment with different antimalarial combinations. The atypical Myosin A motor (PfMyoA) is part of a core macromolecular complex called the glideosome, essential for Plasmodium parasite mobility and therefore an attractive drug target. Here, we characterize the interaction of a small molecule (KNX-002) with PfMyoA. KNX-002 inhibits PfMyoA ATPase activity in vitro and blocks asexual blood stage growth of merozoites, one of three motile Plasmodium life-cycle stages. Combining biochemical assays, X-ray crystallography and molecular dynamics, we demonstrate that KNX-002 targets a novel pocket in PfMyoA, sequestering it in a post-rigor state detached from actin. KNX-002 binding affects Mg 2+ coordination near ATP, preventing ATP hydrolysis and thus inhibiting motor activity. This first-in-class small-molecule inhibitor of PfMyoA paves the way for developing a new generation of antimalarial treatments.

Dates et versions

hal-03811821 , version 1 (12-10-2022)

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Dihia Moussaoui, James Robblee, Daniel Auguin, Fabio Fisher, Patricia Fagnant, et al.. Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design. 2022. ⟨hal-03811821⟩
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