Inhibition of Protein N-Glycosylation Blocks SARS-CoV-2 Infection

Casas Sanchez, Aitor ORCID: https://orcid.org/0000-0001-5237-1223, Romero Ramirez, Alessandra, Hargreaves, Eleanor, Ellis, Cameron C, Grajeda, Brian I, Estevao, Igor L, Patterson, Ian ORCID: https://orcid.org/0000-0003-3465-0848, Hughes, Grant ORCID: https://orcid.org/0000-0002-7567-7185, Almeida, Igor C, Zech, Tobias and Acosta-Serrano, Alvaro ORCID: https://orcid.org/0000-0002-2576-7959 (2022) 'Inhibition of Protein N-Glycosylation Blocks SARS-CoV-2 Infection'. mBio, Vol 13, Issue 1, e0371821.

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Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) extensively glycosylates its spike proteins, which are necessary for host cell invasion and the target of both vaccines and immunotherapies. These glycans are predicted to modulate spike binding to the host receptor by stabilizing its open conformation and host immunity evasion. Here, we investigated the essentiality of both the host -glycosylation pathway and SARS-CoV-2 glycans for infection. Ablation of host glycosylation using RNA interference or inhibitors, including FDA-approved drugs, reduced the spread of the infection, including that of variants B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta). Under these conditions, cells produced fewer virions and some completely lost their infectivity. Furthermore, partial enzymatic deglycosylation of intact virions showed that surface-exposed glycans are critical for cell invasion. Altogether, we propose protein glycosylation as a targetable pathway with clinical potential for treatment of COVID-19. The coronavirus SARS-CoV-2 uses its spike surface proteins to infect human cells. Spike proteins are heavily modified with several -glycans, which are predicted to modulate their function. In this work, we show that interfering with either the synthesis or attachment of spike -glycans significantly reduces the spread of SARS-CoV-2 infection , including that of several variants. As new SARS-CoV-2 variants, with various degrees of resistance against current vaccines, are likely to continue appearing, halting virus glycosylation using repurposed human drugs could result in a complementary strategy to reducing the spread of COVID-19 worldwide.

Item Type:	Article
Subjects:	QU Biochemistry > QU 4 General works QU Biochemistry > Proteins. Amino Acids. Peptides > QU 55 Proteins WC Communicable Diseases > Virus Diseases > Viral Respiratory Tract Infections. Respirovirus Infections > WC 506 COVID-19
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):	https://doi.org/10.1128/mbio.03718-21
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	07 Apr 2022 11:37
Last Modified:	07 Apr 2022 11:37
URI:	https://archive.lstmed.ac.uk/id/eprint/20026

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