Synthesis of the Most Potent Isomer of μ-Conotoxin KIIIA Using Different Strategies

Autor: Xunxun Jian, Yong Wu, Zaoli Mei, Xiaopeng Zhu, Dongting Zhangsun, Sulan Luo
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Molecules, Vol 28, Iss 8, p 3377 (2023)
Druh dokumentu: article
ISSN: 28083377
1420-3049
DOI: 10.3390/molecules28083377
Popis: In the chemical synthesis of conotoxins with multiple disulfide bonds, the oxidative folding process can result in diverse disulfide bond connectivities, which presents a challenge for determining the natural disulfide bond connectivities and leads to significant structural differences in the synthesized toxins. Here, we focus on KIIIA, a μ-conotoxin that has high potency in inhibiting Nav1.2 and Nav1.4. The non-natural connectivity pattern (C1—C9, C2—C15, C4—C16) of KIIIA exhibits the highest activity. In this study, we report an optimized Fmoc solid-phase synthesis of KIIIA using various strategies. Our results indicate that free random oxidation is the simplest method for peptides containing triple disulfide bonds, resulting in high yields and a simplified process. Alternatively, the semi-selective strategy utilizing Trt/Acm groups can also produce the ideal isomer, albeit with a lower yield. Furthermore, we performed distributed oxidation using three different protecting groups, optimizing their positions and cleavage order. Our results showed that prioritizing the cleavage of the Mob group over Acm may result in disulfide bond scrambling and the formation of new isomers. We also tested the activity of synthesized isomers on Nav1.4. These findings provide valuable guidance for the synthesis of multi-disulfide-bonded peptides in future studies.
Databáze: Directory of Open Access Journals
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