Cysteine [2,4] Disulfide Bond as a New Modifiable Site of α-Conotoxin TxIB
Open Access
- 22 February 2021
- journal article
- research article
- Published by MDPI AG in Marine Drugs
- Vol. 19 (2), 119
- https://doi.org/10.3390/md19020119
Abstract
α-Conotoxin TxIB, a selective antagonist of α6/α3β2β3 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 α6/α3β2β3 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 α-Conotoxin TxIB in drug discovery.Keywords
Funding Information
- National Natural Science Foundation of China (No. 81872794)
- Hainan Provincial Natural Science Foundation of China (No. 219QN150, No. KYQD(ZR)1918)
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