Precursors of Viral Proteases as Distinct Drug Targets

Abstract

Viral proteases are indispensable for successful virion maturation, thus making them a prominent drug target. Their enzyme activity is tightly spatiotemporally regulated by expression in the precursor form with little or no activity, followed by activation via autoprocessing. These cleavage events are frequently triggered upon transportation to a specific compartment inside the host cell. Typically, precursor oligomerization or the presence of a co-factor is needed for activation. A detailed understanding of these mechanisms will allow ligands with non-canonical mechanisms of action to be designed, which would specifically modulate the initial irreversible steps of viral protease autoactivation. Binding sites exclusive to the precursor, including binding sites beyond the protease domain, can be exploited. Both inhibition and up-regulation of the proteolytic activity of viral proteases can be detrimental for the virus. All these possibilities are discussed using examples of medically relevant viruses including herpesviruses, adenoviruses, retroviruses, picornaviruses, caliciviruses, togaviruses, flaviviruses, and coronaviruses.

Enzymes in the time of COVID‐19: An overview about the effects in the human body, enzyme market, and perspectives for new drugs

“…Glycomics 223 and lipidomics 224–226 were also exploited. Enzyme structure and possible inhibitors were also investigated 5,16,26,27,156 …”

“…Paulsson‐Habegger, Snabaitis, Wren 15 considered only human enzymes related with SARS‐CoV‐2 entrance in host cell and drugs that can inhibit them. The review presented by Majerová and Novotný 16 does contribute to that field, but its approach is solely on viral proteases, addressing their structures and inhibitors. However, Majerová and Novotný 16 lack a discussion on human enzymes involved in SARS‐CoV‐2 infection, and those three papers do not present an overview on how the enzyme market may benefit from the production of specific medicines against the infection, and from the production of tools to detect the enzymatic alterations that SARS‐CoV‐2 causes on the human body.…”

“…The review presented by Majerová and Novotný 16 does contribute to that field, but its approach is solely on viral proteases, addressing their structures and inhibitors. However, Majerová and Novotný 16 lack a discussion on human enzymes involved in SARS‐CoV‐2 infection, and those three papers do not present an overview on how the enzyme market may benefit from the production of specific medicines against the infection, and from the production of tools to detect the enzymatic alterations that SARS‐CoV‐2 causes on the human body. Also, those three papers do not mention some human enzymes that can, and others hypothesized to, play a role in SARS‐CoV‐2 infection.…”

Mass Spectrometric Assays Reveal Discrepancies in Inhibition Profiles for the SARS‐CoV‐2 Papain‐Like Protease

“…Academic and industrial drug discovery campaigns have focused on developing small‐molecule SARS‐CoV‐2 M pro inhibitors; considerably fewer studies have addressed PL pro inhibition. [ 2a , 2b , 2c , 2d , 2e ] At least to some extent, this might reflect limitations in current in vitro assays that monitor PL pro catalysis. PL pro assays have mostly employed fluorescence‐based methods that measure changes in absorbance/emission wavelengths upon cleavage of a C‐terminal fluorescent tag from a short substrate‐derived peptide, e. g .…”

“…Academic and industrial drug discovery campaigns have focused on developing small‐molecule SARS‐CoV‐2 M pro inhibitors; considerably fewer studies have addressed PL pro inhibition [2a–e] . At least to some extent, this might reflect limitations in current in vitro assays that monitor PL pro catalysis.…”