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

Rodríguez-Hernández, Diego; Vijayan, Kamalakannan; Zigweid, Rachael; Fenwick, Michael K.; Sankaran, Banumathi; Roobsoong, Wanlapa; Sattabongkot, Jetsumon; Glennon, Elizabeth K. K.; Myler, Peter J.; Sunnerhagen, Per; Staker, Bart L.; Kaushansky, Alexis; Grøtli, Morten

doi:10.1038/s41467-023-41119-7

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

Journal Article · Tue Sep 05 00:00:00 EDT 2023 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-41119-7· OSTI ID:2471060

Rodríguez-Hernández, Diego ^[1]; Vijayan, Kamalakannan ^[2]; Zigweid, Rachael ^[3]; ^[3]; ^[4]; ^[5]; ^[5]; Glennon, Elizabeth K. K. ^[6]; ^[7]; ^[8]; Staker, Bart L. ^[3]; ^[9]; ^[8]

University of Gothenburg (Sweden); University of Bergen (Norway)
Indian Institute of Science Education and Research, Kerala (India); Seattle Children’s Research Institute, WA (United States)
Seattle Children’s Research Institute, WA (United States); Seattle Structural Genomics Center for Infectious Disease, WA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Mahidol University, Bangkok (Thailand)
Seattle Children’s Research Institute, WA (United States)
Seattle Children’s Research Institute, WA (United States); Seattle Structural Genomics Center for Infectious Disease, WA (United States); University of Washington, Seattle, WA (United States)
University of Gothenburg (Sweden)
Seattle Children’s Research Institute, WA (United States); University of Washington, Seattle, WA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); National Institute of Allergy and Infectious Diseases, National Institutes of Health; Department of Health and Human Services to support the Seattle Structural Genomics Center for Infectious Disease (SSGCID); Swedish Research Council

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2471060

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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