Nitrile-based peptoids as cysteine protease inhibitors

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Drug Discovery

Background:

• Mammalian cysteine proteases, particularly of the papain superfamily, are crucial drug targets.
• Peptidomimetics offer a promising avenue for developing enzyme inhibitors with improved stability and efficacy.
• Dipeptidyl nitriles represent a class of covalent inhibitors with potential therapeutic applications.

Purpose of the Study:

• To synthesize and characterize novel dipeptidyl nitrile analog peptoids as inhibitors of mammalian cysteine proteases.
• To investigate the structure-activity relationships (SAR) of these peptoids against cruzain and other cathepsins.
• To explore the potential of these peptoids for selective inhibition of specific cysteine proteases.

Main Methods:

• Synthesis of dipeptidyl nitrile analog peptoids with side chains attached to the peptide backbone's nitrogen atom.
• Enzyme inhibition assays to determine affinities (pK_i) against cruzain and various cathepsins (K, L, S, B).
• Structure-activity relationship analysis, including matched molecular pair (MMP) and covalent docking studies.

Main Results:

• Synthesized peptoids demonstrated varying degrees of inhibition against cysteine proteases.
• Compound 4i exhibited high cruzain inhibition (pK_i = 6.8).
• Several peptoids displayed cross-class cathepsin activity (K, L, S), with compounds 4b, 4c, and 4k showing selective, potent inhibition of cathepsin K.
• No significant inhibition was observed against Cathepsin B (CatB).

Conclusions:

• Novel nitrile-based peptoids are effective inhibitors of cysteine proteases, particularly cathepsins.
• The modification of peptide backbones with dipeptidyl nitrile side chains enhances protease resistance and modulates enzyme affinity.
• These findings provide a foundation for designing targeted peptoid-based inhibitors for specific cysteine proteases, excluding CatB.