School of Medicine, Guangxi University, Nanning 530004, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Mar Drugs. 2023 May 26;21(6):326. doi: 10.3390/md21060326.
Conotoxins are a class of disulfide-rich peptides found in the venom of cone snails, which have attracted considerable attention in recent years due to their potent activity on ion channels and potential for therapeutics. Among them, α-conotoxin RgIA, a 13-residue peptide, has shown great promise as a potent inhibitor of α9α10 nAChRs for pain management. In this study, we investigated the effect of substituting the naturally occurring L-type arginine at position 11 of the RgIA sequence with its D-type amino acid. Our results indicate that this substitution abrogated the ability of RgIA to block α9α10 nAChRs, but instead endowed the peptide with the ability to block α7 nAChR activity. Structural analyses revealed that this substitution induced significant alteration of the secondary structure of RgIA[11r], which consequently affected its activity. Our findings underscore the potential of D-type amino acid substitution as a promising strategy for designing novel conotoxin-based ligands targeting different types of nAChRs.
短肽毒素是一类存在于芋螺毒液中的富含二硫键的肽，近年来由于其对离子通道的强大活性和在治疗学上的潜力而受到广泛关注。其中，α-芋螺毒素 RgIA 是一种 13 个氨基酸的肽，作为一种有效的α9α10 nAChR 抑制剂，在疼痛管理方面具有巨大的应用前景。在这项研究中，我们研究了用 D 型氨基酸替代 RgIA 序列中第 11 位天然存在的 L 型精氨酸对其的影响。结果表明，这种取代破坏了 RgIA 阻断α9α10 nAChR 的能力，而是赋予了该肽阻断α7 nAChR 活性的能力。结构分析表明，这种取代诱导了 RgIA[11r]二级结构的显著改变，从而影响了其活性。我们的研究结果强调了 D 型氨基酸取代作为设计针对不同类型 nAChR 的新型芋螺毒素基配体的有前途的策略的潜力。
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