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Comparative Study
. 2021 Feb 22;19(2):119.
doi: 10.3390/md19020119.

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

Baojian Zhang  1 , Maomao Ren  1 , Yang Xiong  1 , Haonan Li  1 , Yong Wu  2 , Ying Fu  1 , Dongting Zhangsun  1   2 , Shuai Dong  1 , Sulan Luo  1   2
Affiliations
Comparative Study

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

Baojian Zhang et al. Mar Drugs. .

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: activity; disulfide bond; high yield; peptidomimetics; α-Conotoxin TxIB.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Six α-Conotoxin TxIB analogs (# signify C-term amidation).
Figure 2
Figure 2
Reagents and conditions. (a) Xylene dibromide, NH4HCO3, ACN-H2O, N2, rt. (b) I2, TFA, ACN-H2O, N2, rt (# signify C-term amidation).
Figure 3
Figure 3
The conversion rate of TxIB[1,3]-L reacted with different ratios of p-xylene dibromide.
Figure 4
Figure 4
HPLC and mass spectrometry results of TxIB[1,3]-L reacted with p-xylene dibromide. (A) HPLC chromatogram of native TxIB with a retention time of 10.68 min. (B) ESI-MS data of native TxIB with a mass of 1739.92 Da. (C) HPLC chromatogram of TxIB[1,3]-p with the retention time of 17.06 min. (D) ESI-MS data of TxIB[1,3]-p with a mass of 1844.12 Da.
Figure 5
Figure 5
The relative membrane currents of TxIB and its analogs at a concentration of 1 μM and 100 μM on rat α6/α3β2β3 nAChR. The negative control was tested by ND-96 solution only. (A) TxIB at 1 μM. (B) TxIB[1,3]-m at 100 μM. (C) TxIB[2,4]-m at 1 μM.
Figure 6
Figure 6
The relative stability of native peptide and the analogs in human serum. Error bars represent the mean ± SEM (n = 3), a taken from ref. [15].
Figure 7
Figure 7
Circular dichroism (CD) spectra of TxIB[1,3]-p and TxIB[2,4]-p compared with native globular TxIB.
Figure 8
Figure 8
Structure of the globular α-Conotoxin TxIB (PDB identifier 2LZ5).
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