PRSS44 Inhibitors

Chemical inhibitors of PRSS44 serve as functional antagonists to its serine protease activity. The inhibition mechanism often involves covalent modification or occupancy of the active site, which is crucial for the catalytic function of PRSS44. AEBSF and 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride operate by forming a covalent bond with the serine residue within the active site of PRSS44. This action blocks the proteolytic cleavage of substrates by PRSS44, thereby inhibiting its function. Phenylmethylsulfonyl fluoride (PMSF) similarly targets the serine residue but does so by reacting with it and forming an irreversible complex, which impedes the enzyme's activity. Compounds such as N-α-Tosyl-L-lysine chloromethyl ketone hydrochloride (TLCK) and N-α-Tosyl-L-phenylalanine chloromethyl ketone (TPCK) inhibit PRSS44 by modifying essential residues that are necessary for substrate binding and catalysis. TLCK is selective for enzymes that recognize lysine, and TPCK targets enzymes with a preference for phenylalanine, which suggests that if PRSS44 has a similar specificity, these inhibitors can directly block its function.

Further inhibitory mechanisms are exhibited by gabexate mesilate, camostat mesilate, and nafamostat mesilate, which are broad-spectrum serine protease inhibitors. They inhibit PRSS44 by occupying its active site, thereby preventing the substrate from accessing the catalytic residues necessary for its hydrolysis. Sivelestat and alvelestat (AZD9668) have a high affinity for neutrophil elastase but can also inhibit PRSS44 by a similar mechanism, assuming structural similarities that allow for the interaction with the active site serine. Ulinastatin, another broad-spectrum inhibitor, binds to PRSS44 and sterically hinders substrate access to the active site. Lastly, ecallantide, known to inhibit kallikrein, can bind to the active site of PRSS44, which would result in a blockade of its protease functionality. Each of these inhibitors employs a distinctive approach to bind and modify the active site of PRSS44, which leads to the inhibition of its proteolytic activity, showing the diverse chemical strategies used to impede the function of serine proteases.