Development 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 A1–13 sequence
as a template for peptide stapling via late-stage cysteine functionalization.
Leveraging this strategy, we developed a stable and potent KOR antagonist,
CSD-CH2(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-expressing
cells, peripheral dorsal root ganglion neurons, and using the tail-flick
and rotarod tests in mice. This work highlights the value of cysteine
stapling to develop selective peptide probes to modulate central KOR
function, as innovative peptide drug candidates for the treatment
of KOR-related illnesses.