Cysteine Proteases: Modes of Activation and Future Prospects as Pharmacological Targets

Abstract

Proteolytic enzymes are crucial for a variety of biological processes in organisms ranging from lower (virus, bacteria, and parasite) to the higher organisms (mammals). Proteases cleave proteins into smaller fragments by catalyzing peptide bonds hydrolysis. Proteases are classified according to their catalytic site, and distributed into four major classes: cysteine proteases, serine proteases, aspartic proteases, and metalloproteases. This review will cover only cysteine proteases, papain family enzymes which are involved in multiple functions such as extracellular matrix turnover, antigen presentation, processing events, digestion, immune invasion, hemoglobin hydrolysis, parasite invasion, parasite egress, and processing surface proteins. Therefore, they are promising drug targets for various diseases. For preventing unwanted digestion, cysteine proteases are synthesized as zymogens, and contain a prodomain (regulatory) and a mature domain (catalytic). The prodomain acts as an endogenous inhibitor of the mature enzyme. For activation of the mature enzyme, removal of the prodomain is necessary and achieved by different modes. The pro-mature domain interaction can be categorized as protein–protein interactions (PPIs) and may be targeted in a range of diseases. Cysteine protease inhibitors are available that can block the active site but no such inhibitor available yet that can be targeted to block the pro-mature domain interactions and prevent it activation. This review specifically highlights the modes of activation (processing) of papain family enzymes, which involve auto-activation, trans-activation and also clarifies the future aspects of targeting PPIs to prevent the activation of cysteine proteases.

Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes

“…3.1. The inhibition of MERS-CoV and SARS-CoV PL pro s by disulfiram PL pro s are cysteine proteases that use the thiol group of cysteine as a nucleophile to attack the carbonyl group of the scissile peptide bond Han et al, 2005;Verma et al, 2016). Inhibition can be expected if the catalytic cysteine of a PL pro is interfered with or modified (Cheng et al, 2015;Chou et al, 2008).…”

Structural characterization of the hypothetical protein Lpg2622, a new member of the C1 family peptidases from Legionella pneumophila

“…Cathepsin L‐like enzymes have a propeptide including 100 residues consists of a short β strand (β1) and three α‐helices (α1, α2, α3) forming similar super‐secondary structure with cathepsin B‐like enzymes (Fig. C) . Taking cathepsin K as an example, the S2′ and S1′ subsites are occupied by Met75 and Thr76, respectively.…”

Hepatitis E Virus Cysteine Protease Has Papain Like Properties Validated by in silico Modeling and Cell-Free Inhibition Assays

“…The protease activity was found to be optimal at low pH of 4 which is the crucial factor to activate Papain like cysteine proteases (Richau et al, 2012;Sundararaj et al, 2012). A number of reports have shown that cysteine proteases can be auto catalytically activated in vitro from zymogen to mature enzyme even at reduced pH (Lowther et al, 2009;Sundararaj et al, 2012;Verma et al, 2016) indicating it to be a cysteine protease. In an attempt to validate the nature of the protease we used various inhibitors to monitor its activity.…”

“…To further know the active site residue involved in the interaction between HEV-protease with inhibitors, its 3D structure has been modeled which also showed the nature of the HEVprotease. The predicted model showed two domains architecture, N-terminal helix and C-terminal β-sheet domain similar to papain-like cysteine proteases (Verma et al, 2016) but differ in arrangement of secondary structure elements. An active site (catalytic pocket) for substrate binding was present between two domains.…”