Cysteine [2,4] Disulfide Bond as a New Modifiable Site of ?-Conotoxin TxIB.

ABSTRACT: ?-Conotoxin TxIB, a selective antagonist of ?6/?3?2?3 nicotinic acetylcholine receptor, could be a potential therapeutic agent for addiction and Parkinson's disease. As a peptide with a complex pharmacophoric conformation, it is important and difficult to find a modifiable site which can be modified effectively and efficiently without activity loss. In this study, three xylene scaffolds were individually reacted with one pair of the cysteine residues ([1,3] or [2,4]), and iodine oxidation was used to form a disulfide bond between the other pair. Overall, six analogs were synthesized with moderate isolated yields from 55% to 65%, which is four times higher than the traditional two-step oxidation with orthogonal protection on cysteines. The cysteine [2,4] modified analogs, with higher stability in human serum than native TxIB, showed obvious inhibitory effect and selectivity on ?6/?3?2?3 nicotinic acetylcholine receptors (nAChRs), which was 100 times more than the cysteine [1,3] modified ones. This result demonstrated that the cysteine [2,4] disulfide bond is a new modifiable site of TxIB, and further modification can be a simple and feasible strategy for the exploitation and utilization of ?-Conotoxin TxIB in drug discovery.

SUBMITTER: Zhang B 

PROVIDER: S-EPMC7926623 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature