蛋白酵素
激肽释放酶
蛋白酶
丝氨酸蛋白酶
噬菌体展示
化学
肽库
肽
体内
蛋白酶抑制剂(药理学)
淘选
生物化学
分子生物学
肽序列
酶
生物
免疫学
人类免疫缺陷病毒(HIV)
基因
抗逆转录病毒疗法
病毒载量
生物技术
作者
Patrick Gonschorek,Alessandro Zorzi,Tamara Maric,Mathilde Le Jeune,Mischa Schüttel,Mathilde Montagnon,Rebeca Gómez-Ojea,Denis Patrick Vollmar,Chantal Whitfield,Luc Reymond,Vanessa Carle,Hitesh Verma,Oliver Schilling,Alain Hovnanian,Christian Heinis
标识
DOI:10.1021/acs.jmedchem.2c00306
摘要
Kallikrein-related peptidases 5 (KLK5) and 7 (KLK7) are serine proteases with homeostatic functions in the epidermis that play a critical role in Netherton syndrome (NS), a rare yet life-threatening genetic disorder that currently lacks specific treatment. Previous research suggests that controlling KLKs could lead to the development of NS therapies, but existing synthetic inhibitors have limitations. Herein, we used phage display to screen libraries comprising more than 100 billion different cyclic peptides and found selective, high-affinity inhibitors of KLK5 (Ki = 2.2 ± 0.1 nM) and KLK7 (Ki = 16 ± 4 nM). By eliminating protease-prone sites and conjugating the inhibitors to an albumin-binding peptide, we enhanced the inhibitor stability and prolonged the elimination half-life to around 5 h in mice. In tissue sections taken from mice, a fluorescently labeled peptide was detected in the epidermis, suggesting that the inhibitors can reach the KLKs upon systemic delivery and should be suited to control deregulated protease activity in NS.
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