title: Toxin acidic residue evolutionary function-guided design of de novo peptide drugs for the immunotherapeutic target, the Kv1.3 channel.
abstract: During the long-term evolution of animal toxins acting on potassium channels, the acidic residues can orientate the toxin binding interfaces by adjusting the molecular polarity. Based on the evolutionary function of toxin acidic residues, de novo peptide drugs with distinct binding interfaces were designed for the immunotherapeutic target, the Kv1.3 channel. Using a natural basic toxin, BmKTX, as a template, which contains 2 acidic residues (Asp19 and Asp33), we engineered two new peptides BmKTX-19 with 1 acidic residue (Asp33), and BmKTX-196 with 2 acidic residues (Asp6 and Asp33) through only adjusting acidic residue distribution for reorientation of BmKTX binding interface. Pharmacological experiments indicated that BmKTX-19 and BmKTX-196 peptides were specific inhibitors of the Kv1.3 channel and effectively suppressed cytokine secretion. In addition to the structural similarity between the designed and native peptides, both experimental alanine-scanning mutagenesis and computational simulation further indicated that the binding interface of wild-type BmKTX was successfully reoriented in BmKTX-19 and BmKTX-196, which adopted distinct toxin surfaces as binding interfaces. Together, these findings indicate not only the promising prospect of BmKTX-19 and BmKTX-196 as drug candidates but also the desirable feasibility of the evolution-guided peptide drug design for discovering numerous peptide drugs for the Kv1.3 channel.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Zongyun
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Youtian
authors.initials: Y
authors.lastname: Hu
authors.affiliation: College of Biological Science and Technology, Fuzhou University, Fuzhou 350108, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hong
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Weishan
authors.initials: W
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xiang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Zili
authors.initials: Z
authors.lastname: Xie
authors.affiliation: 1] State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China [2] Center for BioDrug Research, Wuhan University, Wuhan 430072, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: 1] State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China [2] Center for BioDrug Research, Wuhan University, Wuhan 430072, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.affiliation: College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
authors.forename: Donghai
authors.initials: D
authors.lastname: Lin
authors.affiliation: 1] State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China [2] Center for BioDrug Research, Wuhan University, Wuhan 430072, China.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D024342:Amino Acids, Acidic / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D015195:Drug Design; D019143:Evolution, Molecular; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000187:drug effects; D010455:Peptides / Q000737:chemistry*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D012604:Scorpion Venoms / Q000737:chemistry; D012996:Solutions; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D024342:Amino Acids, Acidic; D016207:Cytokines; C109066:KTX toxin, Buthus; D051664:Kv1.3 Potassium Channel; D010455:Peptides; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; D012996:Solutions