Peptide stapling with the retention of double native side-chains  

作　　者：Ye Wu Yan Zou Lingling Sun Alfredo Garzino-Demo Honggang Hu Weidong Zhang Xiang Li 

机构地区：[1]Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China [2]School of Pharmacy,Second Military Medical University,Shanghai 200433,China [3]Institute of Human Virology and Department of Microbiology and Immunology,University of Maryland School of Medicine,Baltimore MD 21201,United States [4]Department of Molecular Medicine,University of Padova,Padova 35121,Italy [5]Institute of Translational Medicine,Shanghai University,Shanghai 200444,China

出　　处：《Chinese Chemical Letters》2021年第12期4045-4048,共4页中国化学快报（英文版）

基　　金：supported by the National Key R&D Program of China (No. 2019YFC1711000, to X. Li);the National Nature Science Foundation of China (No. 21807112, to X. Li;No. 91849129, to H. Hu;No. 22077078, to H. Hu);Shanghai Rising-Star Program (to X. Li)。

摘　　要：All-hydrocarbon stapling strategy has been widely applied for enhancing the proteolytic stability of peptides. However, two major technical hurdles to some extent limit the development of stapled peptides for therapeutic usage: rational selection of the stapling sites and the corresponding deletion of the native side chains. Previously we described the development of the olefin-terminated amino acids with the retention of native side chains and successfully applied them in the synthesis of hydrocarbon stapled peptides with single side-chain retention. Here, we explored the feasibility and effectiveness of hydrocarbon stapling strategy characterized as double side-chains retention. Modeled after a lengthy human immunodeficiency virus-1(HIV-1) fusion inhibitor SC34 EK, Leu^(i), Ser^(i+4)and Lys^(i), Leu^(i+4)stapled peptides with the retention of double side-chains were effectively obtained. Our complementary study provided a convenient alternative to address where to install the staple in sequence for conventional all-hydrocarbon peptide stapling. Furthermore, this method not only conferred conformational reinforcement for SC34 EK with high α-helicity and protease resistance, but also preserved the structural characteristic(key peripheral residues, charge and solubility) of the linear peptide to the maximum, which are crucial for anti-HIV-1 activity.

关 键 词：Stapling strategy Stapled peptide Native side chain Peptide drug design HIV-1 fusion inhibitor SC34EK 

分 类 号：TQ464.7[化学工程—制药化工]