Serine protease mimetics

Serine Protease Mimetics - Histidine-Serine/Threonine/ Cysteine-Carboxylate - Systems (Catalytic Triads N OH/SH CO-)... 

Despite the ubiquitous nature of serine proteases, it is possible to design specific thrombin inhibitors by taking advantage of the accessory regulatory binding sites on the enzyme surface. The inibitors are efficacious in several experimental models of thrombosis, and above all, illustrate the feasibility of low molecular weight protein mimetics. 

Chymotrypsin and V8 peptidase, members of the trypsin family of serine proteases, as well as an engineered trypsin variant (D189K/K60E), were employed for the N-terminal introduction of 2-aminobenzoyl- and 3-(4-hydroxy-phenyl)-propionyl groups, and biotin in the form of substrate mimetics into peptides [115]. 

Other potent peptide mimetic NS3 protease inhibitors have been reported that incorporate a serine trap on the C-terminal end of the peptide. Thus, the inhibitory activity of telaprevir (VX-950, 59), (7nM vs. NS3, 300 nM vs. the la replicon) is based on truncation of the polypeptide substrate, maximizing binding by alteration of amino acids at the scissile site, and capping both N- and C-terminal ends, the latter with a known dicarbonyl serine trap. This compound has exhibited impressive antiviral activity in animals, and showed a 4.4 log drop in viral load in genotype 1-infected patients in a Phase lb clinical trial [110]. Telaprevir is expected to enter Phase 3 clinical trials in 2007. Additional bicyclo-proline-based P2 tetrapeptides, represented by analog 60 (Kj = 22 nM), have been explored. Although the compounds are selective inhibitors of NS3, little or no cell-based replicon activity was reported, presumably due to poor cellular permeability [111-114], A diastereomer of telaprevir, has been reported to inhibit the replicon with an EC50 of 0.55 pM [115]. 

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