Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts.

Autor: Rodríguez-Hernández D; Department of Chemistry and Molecular Biology, University of Gothenburg; S-405 30, Gothenburg, Sweden.; Department of Chemistry, University of Bergen, Allegaten 41, NO-5007, Bergen, Norway., Vijayan K; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98109, USA.; School of Biology, Indian Institute of Science Education and Research, Thiruvananthapuram, Kerala, 695551, India., Zigweid R; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98109, USA.; Seattle Structural Genomics Center for Infectious Disease, Seattle, WA, 98109, USA., Fenwick MK; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98109, USA.; Seattle Structural Genomics Center for Infectious Disease, Seattle, WA, 98109, USA., Sankaran B; Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Advanced Light Source; Berkeley National Laboratory, Berkeley, CA, 94720, USA., Roobsoong W; Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand., Sattabongkot J; Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand., Glennon EKK; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98109, USA., Myler PJ; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98109, USA.; Seattle Structural Genomics Center for Infectious Disease, Seattle, WA, 98109, USA.; Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA., Sunnerhagen P; Department of Chemistry and Molecular Biology, University of Gothenburg; S-405 30, Gothenburg, Sweden., Staker BL; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98109, USA.; Seattle Structural Genomics Center for Infectious Disease, Seattle, WA, 98109, USA., Kaushansky A; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98109, USA. Alexis.Kaushansky@seattlechildrens.org.; Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA. Alexis.Kaushansky@seattlechildrens.org., Grøtli M; Department of Chemistry and Molecular Biology, University of Gothenburg; S-405 30, Gothenburg, Sweden. grotli@chem.gu.se.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Sep 05; Vol. 14 (1), pp. 5408. Date of Electronic Publication: 2023 Sep 05.
DOI: 10.1038/s41467-023-41119-7
Abstrakt: Drugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce the health and economic burdens caused by malaria worldwide. N-myristoyltransferase (NMT) is an essential eukaryotic enzyme and a validated drug target for combating malaria. However, previous PvNMT inhibitors have failed due to their low selectivity over human NMTs. Herein, we apply a structure-guided hybridization approach combining chemical moieties of previously reported NMT inhibitors to develop the next generation of PvNMT inhibitors. A high-resolution crystal structure of PvNMT bound to a representative selective hybrid compound reveals a unique binding site architecture that includes a selective conformation of a key tyrosine residue. The hybridized compounds significantly decrease P. falciparum blood-stage parasite load and consistently exhibit dose-dependent inhibition of P. vivax liver stage schizonts and hypnozoites. Our data demonstrate that hybridized NMT inhibitors can be multistage antimalarials, targeting dormant and developing forms of liver and blood stage.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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