Targeting the viral-entry facilitators of SARS-CoV-2 as a therapeutic strategy in COVID-19

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) infection, which has emerged as a global pandemic causing serious concerns. Lack of specific and effective therapeutics for the treatment of COVID-19 is a major concern and the development of vaccines is another important aspect in managing the infection effectively. The first step in the SARS-CoV-2 pathogenesis is the viral entry and it is mediated by its densely glycosylated spike protein (S-protein). Similar to the SARS-CoV, SARS-CoV-2 also engages angiotensin-converting enzyme 2 (ACE2) as the host cell entry receptor. In addition to ACE2, several recent studies have implicated the crucial role of cell surface heparan sulfate (HS) as a necessary assisting cofactor for ACE2-mediated SARS-CoV-2 entry. Furthermore, SARS-CoV-2 was also identified to use both endosomal cysteine proteases cathepsin B and L (CatB/L) and the transmembrane serine protease 2 (TMPRSS2) for the pivotal role of S-protein priming mediating viral entry. As the entry of SARS-CoV-2 into host cells is mandatory for viral infection, it becomes an extremely attractive therapeutic intervention point. In this regard, this review will focus on the therapeutic targeting of the crucial steps of SARS-CoV-2 viral entry like S-protein/ACE2 interaction and S-protein priming by host cell proteases. In addition, this review will also give insights to the readers on several therapeutic opportunities, pharmacological targeting of the viral-entry facilitators like S-Protein, ACE2, cell surface HS, TMPRSS2, and CatB/L and evidence for those drugs currently ongoing clinical studies.

Keywords: ACE2; CatB/L; S-protein; SARS-CoV-2; TMPRSS2; clinical trials; heparan sulfate.

Figure 1

Life cycle of SARS‐CoV‐2. ACE2, angiotensin‐converting enzyme 2; CatL, cathepsin L; E‐protein, envelope protein; HSPG, heparan sulfate proteoglycans; M‐protein, membrane glycoprotein; N‐protein, nucleocapsid protein; ORF1a, open‐reading frame 1a; ORF1ab, open‐reading frame 1ab; RER, rough endoplasmic reticulum; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2; S‐protein, spike protein; TMPRSS2, transmembrane serine protease 2

Figure 2

Targeting the viral‐entry facilitators of SARS‐CoV‐2 infection. SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2