Host Cell Proteases Involved in Human Respiratory Viral Infections and Their Inhibitors: A Review

Abstract

Viral tropism is most commonly linked to receptor use, but host cell protease use can be a notable factor in susceptibility to infection. Here we review the use of host cell proteases by human viruses, focusing on those with primarily respiratory tropism, particularly SARS-CoV-2. We first describe the various classes of proteases present in the respiratory tract, as well as elsewhere in the body, and incorporate the targeting of these proteases as therapeutic drugs for use in humans. Host cell proteases are also linked to the systemic spread of viruses and play important roles outside of the respiratory tract; therefore, we address how proteases affect viruses across the spectrum of infections that can occur in humans, intending to understand the extrapulmonary spread of SARS-CoV-2.

Keywords: SARS-CoV-2; protease inhibitors; proteases; respiratory proteases; viruses.

Figure 1

Substrate (left) cleaved by protease (right) with the scissile bond marked by an arrow.

Figure 2

Furin cleavage of influenza HA and SARS-CoV-2 S. HA has one cleavage site (CS) while S has two (S1/S2 and S2′). The location of the fusion peptide of each glycoprotein is indicated by FP.

Figure 3

Artistic representation of one monomeric unit of SARS-CoV-2 S being cleaved by furin and then entering into the “up” conformation with the receptor binding domain exposed.

Figure 4

Illustration of the different types of inhibition.