Synthesis and biological evaluation of S-lipidated lipopeptides of a connexin 43 channel inhibitory peptide

RSC Med Chem. 2020 Jul 10;11(9):1041-1047. doi: 10.1039/d0md00172d. eCollection 2020 Sep 1.


The synthesis and biological activity of 42 novel S-lipidated analogues of a connexin 43 channel inhibitory Peptide5 is described. Unmodified Peptide5 moderates hemichannels and gap junctions that are both implicated in the progression of neurological disease. Peptide5 was site-specifically modified with a cysteine residue, which then underwent thiol-ene mediated S-lipidation to afford S-lipidated Peptide5 analogues containing straight-chain, branched, or aromatic lipids. The modified peptides were assessed for their effect on hemichannel opening and the most promising candidates were evaluated in serum stability studies.