靶向瞬时受体电位香草酸亚型1离子通道的Nplus-RhTx多肽抑制剂理性设计及功能验证  

Design,synthesis and functional validation of peptide inhibitors based on TRPV1 ion channel agonist RhTx

作　　者：张恒 王嘉薇 杨帆[1] ZHANG Heng;WANG Jiawei;YANG Fan(Department of Biophysics,School of Basic Medical Sciences,Zhejiang University School of Medicine,Hangzhou 310058,China)

机构地区：[1]浙江大学医学院基础医学院生物物理系,浙江杭州310058

出　　处：《浙江大学学报（医学版）》2024年第2期201-206,共6页Journal of Zhejiang University(Medical Sciences)

基　　金：国家自然科学基金(32122040,31971040);中国博士后创新人才支持计划(BX20230323)。

摘　　要：目的:获得靶向瞬时受体电位香草酸亚型1(TRPV1)通道的多肽抑制剂。方法:基于已有的靶向TRPV1通道的多肽激动剂红头蜈蚣毒素(RhTx)进行理性设计,在其氨基末端增加带正电荷的氨基酸,并在细胞上使用膜片钳电生理验证设计的多肽对TRPV1通道的抑制作用。结果:理性设计了8条Nplus-RhTx多肽,在膜片钳电生理记录中发现其中4条可以抑制TRPV1的辣椒素激活,4条Nplus-RhTx多肽的半数有效抑制浓度分别为(188.3±4.7)、(193.6±18.0)、(282.8±11.9)和(299.5±6.4)µmol/L。结论:通过对RhTx多肽的氨基端进行理性设计改变其性质,可获得靶向TRPV1的多肽抑制剂。Objective:To design and synthesize peptide inhibitors targeting transient receptor potential vanilloid 1(TRPV1)ion channel,and to validate their function.Methods:Based on previous studies on the relation of molecular structure and function of red head toxin(RhTx),a series of peptides were rationally designed and synthesized,with positive charged amino acids linked to the N terminus of RhTx.These Nplus-RhTx peptides were functionally validated by patch-clamp recordings in live cells.Results:Among the 8 synthesized Nplus-RhTx peptides,four inhibited TRPV1 ion channel activated by capsaicin with IC50 of(188.3±4.7),(193.6±18.0),(282.8±11.9)and(299.5±6.4)µmol/L,respectively.Conclusion:It is feasible to develop TRPV1 peptide inhibitors by using rational design based on N terminal residues of RhTx.

关 键 词：瞬时受体电位香草酸亚型1 离子通道 多肽 理性设计 电生理 

分 类 号：R96[医药卫生—药理学]