Targeting heparan sulfate proteoglycan-assisted endocytosis as a COVID-19 therapeutic option

BioRxiv : the Preprint Server for Biology
Qi ZhangYihong Ye

Abstract

Drugs capable of blocking the infectious cycle of the coronavirus SARS-CoV-2 are urgently needed to tackle the ongoing COVID-19 pandemic. To this end, the cell entry of SARS-CoV-2, initiated by the binding of the viral Spike (S) protein to human ACE2, has emerged as an attractive drug repurposing target. Here we use murine leukemia viruses pseudotyped with Spike from SARS-CoV or SARS-CoV-2 to demonstrate that ACE2-mediated coronavirus entry can be mitigated by heparin, a heparan sulfate-related glycan, or by genetic ablation of biosynthetic enzymes for the cell surface heparan sulfate proteoglycans (HSPGs). A drug repurposing screen targeting HSPG-dependent endocytosis identifies pharmacologically active endocytosis inhibitors that also abrogate coronavirus cell entry. Among them, Mitoxantrone (EC 50 =~10 nM) targets HSPGs directly, whereas Sunitinib and BNTX disrupt the actin network to impair HSPG-assisted viral entry. Gene expression profiling suggests potential combination regimens that optimally target HSPG-dependent viral entry. Altogether, our study establishes HSPGs as an assisting factor for ACE2 in endocytosis-mediated coronavirus entry and identifies drugs that can be repurposed to target this important stage in the ...Continue Reading

Citations

Nov 27, 2020·Journal of Clinical Medicine·Jay TrivediSiddappa N Byrareddy
Apr 19, 2021·TH Open : Companion Journal to Thrombosis and Haemostasis·Anke PapeReinhard Brunkhorst

Methods Mentioned

BETA
pulldown
gene knockdown
Fluorescence
transfection
RNAseq

Related Concepts

Related Feeds

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.