Publikationsrepositorium - Helmholtz-Zentrum Dresden-Rossendorf
1 PublikationDipeptide-derived alkynes as potent and selective irreversible inhibitors of cysteine cathepsins
Behring, L.; Ruiz-Gomez, G.; Trapp, C.; Morales, M.; Wodtke, R.; Köckerling, M.; Kopka, K.; Pisabarro, M. T.; Pietzsch, J.; Löser, R.
Abstract
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 homogenous products obtained in the Gilbert-Seyferth homologation for C-C triple bond formation. 23 dipeptide alkynes and 12 analogous nitriles were synthesized and investigated for their inhibition of cathepsins B, L, S and K. Numerous combinations of residues in the P1 and P2 positions 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 more than three orders of magnitude (3-10,133 M-1<\sup>s-1<\sup>). 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.
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Data files for determination of inhibitory potency of the published compounds …
ROBIS: 36587 is a supplement to this (Id 35046) publication -
Data files for determination of inhibitory potency of the published compounds …
ROBIS: 36587 HZDR-primary research data are used by this (Id 35046) publication -
Data files for determination of inhibitory potency of the published compounds …
RODARE: 2166 HZDR-primary research data are used by this (Id 35046) publication
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Journal of Medicinal Chemistry 66(2023)6, 3818-3851
DOI: 10.1021/acs.jmedchem.2c01360
Cited 3 times in Scopus
Permalink: https://www.hzdr.de/publications/Publ-35046