Inhibition of host N-myristoylation compromises the infectivity of SARS-CoV-2 due to Golgi-bypassing egress PMID: 42115621

Target-related Cytokines

2026-09-23

Inhibition of host N-myristoylation compromises the infectivity of SARS-CoV-2 due to Golgi-bypassing egress

Nat Commun. 2026 May 11. doi: 10.1038/s41467-026-72938-z.

Saber H Saber ^# ¹ ² ³ , Nyakuoy Yak ^# ¹ ² , Konstantin Dolski ⁴ , Sanna Mäki ⁴ , Lev Levanov ⁴ , Levina A Willenbrink ⁴ , Julian D J Sng ⁵ , Mohammed R Shaker ¹ , Sean D Morrison ¹ , Huiwen Zheng ¹ , Selin Pars ¹ , Giovanni Pietrogrande ¹ , Yih Tyng Bong ⁴ , Tania Vane-Tempest ⁴ , Teemu Smura ⁴ , Tomas Strandin ⁴ , Ravi Ojha ⁴ , Ravi Kant ⁴ ⁶ ⁷ , Janika Ruuska ⁴ , Francesco Topi ⁴ , Diana Vaskiv ⁴ , Lauri Kareinen ⁴ ⁸ , Tobias Binder ¹ , Siyuan Lu ¹ , Matthias Floetenmeyer ⁹ , Bahaa Al-Mhanawi ¹ , Yanshan Zhu ⁵ , Tarja Sironen ⁴ ⁶ , Gert Hoy Talbo ¹ , Kirsty R Short ⁵ , Wouter W Kallemeijn ¹⁰ ¹¹ , Roberto Solari ¹² , Jessica Mar ¹ , Edward W Tate ¹⁰ ¹¹ , Ashley J van Waardenberg ¹³ , Olli Vapalahti ⁴ ⁶ ¹⁴ , Ernst Wolvetang ¹⁵ , Giuseppe Balistreri ¹⁶ ¹⁷ , Merja Joensuu ¹⁸

Affiliations

1. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia.
2. Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
3. Department of Zoology, Faculty of Science, Assiut University, Assiut, Egypt.
4. Department of Virology, Medicum Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
5. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
6. Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.
7. Department of Tropical Parasitology, Institute of Maritime and Tropical Medicine, Medical University of Gdansk, Gdańsk, Poland.
8. Finnish Food Authority, Helsinki, Finland.
9. Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, Australia.
10. The Francis Crick Institute, London, United Kingdom.
11. Department of Chemistry, Imperial College London, London, United Kingdom.
12. Myricx Bio, London, United Kingdom.
13. i-Synapse, Cairns, Australia.
14. HUS Diagnostic Center, Clinical Microbiology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
15. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia. [email protected].
16. Department of Virology, Medicum Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. [email protected].
17. Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland. [email protected].
18. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia. [email protected].
# Contributed equally.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic, remains a global health concern despite vaccines, neutralizing antibodies, and Antiviral drugs. The emergence of viral mutations that diminish the effectiveness of current interventions underscores the importance of alternative, host-directed strategies. Here, we show that pharmacological inhibition or knockdown of host N-myristoyltransferase 1 (NMT1), one of the two human Enzymes that mediates protein N-myristoylation, significantly impairs SARS-CoV-2, Vesicular Stomatitis Virus (VSV) and Respiratory syncytial virus (RSV) infections. We demonstrate the Antiviral efficacy and safety of this host-directed therapeutic strategy across multiple viral tropic sites, including human Lung Adenocarcinoma cell lines, primary nasal epithelial cells, and human choroid plexus-cortical brain organoids. NMT1 inhibition triggers a Golgi-bypassing pathway for SARS-CoV-2 progeny virion egress, through endoplasmic reticulum and lysosomal structures, which leads to perturbed progeny virion composition and spike maturation, impairing progeny virion infectivity.