Nitrile-based peptoids as cysteine protease inhibitors.

Peptidomimetics of the class of dipeptidyl nitrile analog peptoids were synthesized as inhibitors of mammalian cysteine proteases of the papain superfamily. The dipeptidyl nitrile side chains were attached to the peptide backbone's nitrogen atom, not to the α-carbons. Synthesized nitrile-based peptoid analogs that lack the hydrogen amide at P2-P3 are responsible for many of the secondary structure elements in peptides and proteins, making them resistant to proteolysis. The designed peptoids would lose a hydrogen bond with cruzain Asp161 decreasing the affinity toward the enzyme. A structure-activity relationship and matched molecular pair-based analysis between the dipeptidyl nitrile Neq0409 and its peptoid 4a yielded the following cruzain affinities: pKiNeq0409 = 6.5 and pKi4a = 5.2. respectively. A retrosynthetic matched molecular pair cliff (RMMP-cliff) analysis with a ΔpKiNeq0409-4a of 1.3 log is found for this transformation. These novel peptoids were then optimized, leading to compound 4i, with high cruzain inhibition (pKi = 6.8). Cross-class cathepsin activity was observed for some of these novel compounds against cathepsins K, L and S, while other compounds presented a selective inhibition of cathepsin K (4b, 4c, 4k) over ten times higher than the other enzymes. The putative mode of binding was determined by using covalent docking, which also aided to describe the structure-activity relationship (SAR). Interestingly, none of the peptoids inhibited CatB to any appreciable extent. These results provide guidance to identify novel bioactive nitrile-based peptoids.

Synthesis, biochemical evaluation and molecular modeling studies of nonpeptidic nitrile-based fluorinated compounds.

Aim: Compounds that block enzyme activity can kill pathogens and help develop effective and safe drugs for Chagas disease and leishmaniasis. Materials & methods: A library of nonpeptidic nitrile-based compounds was synthesized and had their inhibitory affinity tested against cruzain, Leishmania mexicana cysteine protease B and cathepsin L. Isothermal titration calorimetry experiments and molecular simulations were performed for selected compounds to obtain thermodynamic fingerprints and identify main interactions and putative modes of binding with cruzain. Results: The derivatives provided increased affinity against all enzymes compared with the lead, and thermodynamic and computational studies showed improved thermodynamic properties and a possible different mode of binding. Conclusion: Our studies culminated in 1b, a compound 60-fold more potent in cruzain than its lead that also showed entropic and enthalpic contributions favorable to Gibbs binding energy.