Dipeptide-Derived Alkynes as Potent and Selective Irreversible Inhibitors of Cysteine Cathepsins

Research output: Contribution to journalResearch articleContributedpeer-review



The potential of designing irreversible alkyne-based inhibitors of cysteine cathepsins by isoelectronic replacement in reversibly acting potent peptide nitriles was explored. The synthesis of the dipeptide alkynes was developed with special emphasis on stereochemically homogeneous products obtained in the Gilbert-Seyferth homologation for C≡C bond formation. Twenty-three dipeptide alkynes and 12 analogous nitriles were synthesized and investigated for their inhibition of cathepsins B, L, S, and K. Numerous combinations of residues at positions P1 and P2 as well as terminal acyl groups allowed for the derivation of extensive structure-activity relationships, which were rationalized by computational covalent docking for selected examples. The determined inactivation constants of the alkynes at the target enzymes span a range of >3 orders of magnitude (3-10 133 M-1 s-1). Notably, the selectivity profiles of alkynes do not necessarily reflect those of the nitriles. Inhibitory activity at the cellular level was demonstrated for selected compounds.


Original languageEnglish
Pages (from-to)3818-3851
Number of pages34
JournalJournal of medicinal chemistry
Issue number6
Publication statusPublished - 23 Mar 2023

External IDs

PubMed 36867428
WOS 000944546800001


ASJC Scopus subject areas


  • Azadipeptide nitrile, B expression, Bestmann-ohira reagent, Covalent inhibitors, Drug discovery, Ethynylglycine synthon, Occluding loop, Prognostic markers, Substrate-specificity, Terminal alkynes, Cysteine, Nitriles/chemistry, Structure-Activity Relationship, Dipeptides/chemistry, Cathepsin B, Cathepsins/metabolism, Cysteine Proteinase Inhibitors/chemistry