Targeting host cell proteases as a potential treatment strategy to limit the spread of SARS-CoV-2 in the respiratory tract

Abstract

As the death toll of Coronavirus disease 19 (COVID-19) continues to rise worldwide, it is imperative to explore novel molecular mechanisms for targeting SARS-CoV-2. Rather than looking for drugs that directly interact with key viral proteins inhibiting its replication, an alternative and possibly add-on approach is to dismantle the host cell machinery that enables the virus to infect the host cell and spread from one cell to another. Excellent examples of such machinery are host cell proteases whose role in viral pathogenesis has been demonstrated in numerous coronaviruses. In this review, we propose two therapeutic modalities to tackle SARS-CoV-2 infections; the first is to transcriptionally modulate the expression of cellular proteases and their endogenous inhibitors and the second is to directly inhibit their enzymatic activity. We present a nonexhaustive collection of clinically investigated drugs that act by one of these mechanisms and thus represent promising candidates for preclinical in vitro testing and hopefully clinical testing in COVID-19 patients.

Keywords: COVID-19; SARS-CoV-2; adjunctive therapy; clinical trial; proteases.

FIGURE 1

An illustration of the two cleavage sites of the Spike (S) proteins of SARS‐CoV‐1 and SARS‐CoV‐2 and the host cell proteases that can possibly cleave them. (A) Schematic representation of SARS‐CoV‐1 S protein with its functional domains (RBD, receptor binding domain; RBM, receptor binding motif; TD, transmembrane domain) and its two proteolytic cleavage sites (S1/S2, S2′). Amino acid sequences around the two protease recognition sites (red) are indicated for both S proteins of SARS‐CoV‐1 and SARS‐CoV‐2 (asterisks indicate conserved residues). Arrowheads indicate the cleavage site. (copied with permission from Figure 1A by Hoffmann and colleagues ⁶ ). (B) A table listing host cell proteases that are reported to cleave S proteins of coronaviruses together with their subcellular locations, classification according to the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC‐IUBMB) and their common recognition sequences with the cleavage site indicated by a downward arrow. Amino acid residues on the N‐terminal end of the cleavage site are designated P1, P2, P3,...etc, while those on the C‐terminal end are designated P1’, P2’, P3’,...etc “X” denotes any amino acid residue, “hydrophobic” denotes Ala, Val, Leu, Ile, Phe, Trp or Tyr, “aromatic” denotes Phe, Trp, His or Tyr and “positive” denotes Lys, Arg or His ⁷

FIGURE 2

A diagram illustrating the different drug candidates, their targets and mechanisms of action. Host cell proteases depicted here are reported to proteolytically cleave the S protein of coronaviruses which is an essential step to initiate the fusion process between viral and epithelial cell membranes. Three categories of drugs are described; drugs that downregulate the expression of protease enzymes, drugs that directly inhibit their enzymatic activity, and drugs that upregulate the expression of endogenous protease inhibitors. All elements used in this illustration come from the Reactome icon library (https://reactome.org/icon‐lib). Protein structures of host cell proteases and protease inhibitors were obtained from UniProt knowledgebase (https://www.uniprot.org/) and Protein Data Bank (https://www.rcsb.org/). Abbreviations: TMPRSS, transmembrane serine protease; HDAC, histone deacetylase; HAI‐1, hepatocyte growth factor activator inhibitor type 1