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

Sung-Hyun Yang; Connor A Clemett; Margaret A Brimble; Simon J O'Carroll; Paul W R Harris

doi:10.1039/d0md00172d

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.

Authors

Sung-Hyun Yang^{1

2}, Connor A Clemett³, Margaret A Brimble^{1

2

4}, Simon J O'Carroll³, Paul W R Harris^{1

2

4}

Affiliations

¹ School of Chemical Sciences , The University of Auckland , 23 Symonds St , Auckland , New Zealand . Email: paul.harris@auckland.ac.nz.
² School of Biological Sciences , The University of Auckland , 3a Symonds St, Private Bag 92019 , Auckland , New Zealand.
³ Department of Anatomy Medical Imaging , School of Medical Sciences , Faculty of Medical and Health Sciences, and Centre for Brain Research , University of Auckland , Private Bag 92019 , Auckland , New Zealand . Email: s.ocarroll@auckland.ac.nz.
⁴ Maurice Wilkins Centre for Molecular Biodiscovery , The University of Auckland , 3a Symonds St , Auckland , New Zealand.

Abstract

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.