Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus

Nature Chemistry
Aurelie MousnierEdward W Tate

Abstract

Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.

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Citations

Aug 22, 2018·Chembiochem : a European Journal of Chemical Biology·Nadine KaiserHerbert Waldmann
Oct 21, 2018·Molecular & Cellular Proteomics : MCP·Andrea Goya GrocinEdward W Tate
Feb 26, 2019·Chembiochem : a European Journal of Chemical Biology·Marco LucchinoRaphaël Rodriguez
Aug 30, 2019·Der Internist·A GrünewaldtG G U Rohde
Feb 28, 2020·Nature Communications·Tatsiana KosciukHening Lin
Sep 25, 2018·Future Virology·Victor CasanovaPeter G Barlow
Jun 6, 2020·Expert Review of Respiratory Medicine·John CafferkeyPatrick Mallia
Nov 23, 2018·Frontiers in Pharmacology·Kak-Ming LingUNKNOWN Australian Respiratory Early Surveillance Team for Cystic Fibrosis
Oct 22, 2019·Nature·Sebastian DollMarcus Conrad
Jan 1, 2019·Molecular & Cellular Proteomics : MCP·Andrea Goya GrocinEdward W Tate
Nov 23, 2020·Current Opinion in Chemical Biology·Ana Losada de la LastraEdward W Tate
Apr 7, 2021·Chemical Reviews·Kiall F SuazoMark D Distefano
Jun 8, 2021·Frontiers in Cell and Developmental Biology·Chee Wai Fhu, Azhar Ali
Jul 20, 2021·Journal of Experimental Pharmacology·James A CoultasSebastian L Johnston
Jun 17, 2020·Journal of Medicinal Chemistry·Alexandre BancetIsabelle Krimm
Aug 10, 2021·Frontiers in Cell and Developmental Biology·Garrison Komaniecki, Hening Lin
Dec 19, 2019·Journal of Medicinal Chemistry·Anke HarupaAlexis Kaushansky
Jan 9, 2020·Journal of Medicinal Chemistry·Daniel A ErlansonPaul N Mortenson

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Datasets Mentioned

BETA
PXD005798

Methods Mentioned

BETA
myristoylation
X-ray
surface plasmon resonance
pull
electrophoresis
pulled down
pull down
PCR
lipidation

Software Mentioned

MaxQuant

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