biostudies-literatureMuratspahic EAustrian Science Fund FWFUniversit?t InnsbruckBundesministerium f?r Bildung, Wissenschaft und ForschungNational Health and Medical Research CouncilAustralian Research Council11843-11854https://www.ebi.ac.uk/biostudies/studies/S-EPMC10510397biostudies-literatureUnknown66(17)The κ-opioid receptor (KOR) is an attractive target for the development of novel drugs. KOR agonists are potentially safer pain medications, whereas KOR antagonists are promising drug candidates for the treatment of neuropsychiatric disorders. Hitherto, the vast majority of selective drug leads that have been developed for KOR are small molecules. In this study, novel peptide probes were designed by using an endogenous dynorphin A_1-13 sequence as a template for peptide stapling via late-stage cysteine functionalization. Leveraging this strategy, we developed a stable and potent KOR antagonist, CSD-CH_2(1,8)-NH₂, with approximately 1000-fold improved selectivity for KOR over μ- and δ-opioid receptors. Its potent competitive KOR antagonism was verified in KOR-Journal of medicinal chemistryDevelopment of a Selective Peptide κ-Opioid Receptor Antagonist by Late-Stage Functionalization with Cysteine Staples.PMC10510397P32109I4697GNT2009564ICM-2019-13441CE200100012Fischer MJMCraik DJCiotu CITomasevic NSpetea MGruber CWMuratspahic EKoehbach JHochrainer NLewis RJWhite AMfalseDevelopment of a Selective Peptide κ-Opioid Receptor Antagonist by Late-Stage Functionalization with Cysteine Staples.The κ-opioid receptor (KOR) is an attractive target for the development of novel drugs. KOR agonists are potentially safer pain medications, whereas KOR antagonists are promising drug candidates for the treatment of neuropsychiatric disorders. Hitherto, the vast majority of selective drug leads that have been developed for KOR are small molecules. In this study, novel peptide probes were designed by using an endogenous dynorphin A_1-13 sequence as a template for peptide stapling via late-stage cysteine functionalization. Leveraging this strategy, we developed a stable and potent KOR antagonist, CSD-CH_2(1,8)-NH₂, with approximately 1000-fold improved selectivity for KOR over μ- and δ-opioid receptors. Its potent competitive KOR antagonism was verified in KOR-2023-01-01T00:00:00Z2023 Sep2025-04-26T04:49:56.326Z2024-12-03T18:25:05.562ZS-EPMC105103973763244710.1021/acs.jmedchem.3c00426