Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia.
Department of Biology, Chemistry and Pharmacy, Institute of Pharmacy, Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195, Berlin, Germany.
Angew Chem Int Ed Engl. 2022 Jan 21;61(4):e202113857. doi: 10.1002/anie.202113857. Epub 2021 Dec 9.
Constrained peptides are promising next-generation therapeutics. We report here a fundamentally new strategy for the facile generation of bicyclic peptides using linear precursor peptides with three cysteine residues and a non-toxic trivalent bismuth(III) salt. Peptide-bismuth bicycles form instantaneously at physiological pH, are stable in aqueous solution for many weeks, and much more resistant to proteolysis than their linear precursors. The strategy allows the in situ generation of bicyclic ligands for biochemical screening assays. We demonstrate this for two screening campaigns targeting the proteases from Zika and West Nile viruses, revealing a new lead compound that displayed inhibition constants of 23 and 150 nM, respectively. Bicyclic peptides are up to 130 times more active and 19 times more proteolytically stable than their linear analogs without bismuth.
约束肽是很有前途的下一代治疗药物。我们在这里报告了一种使用带有三个半胱氨酸残基的线性前体肽和无毒的三价三价铋(III)盐轻松生成双环肽的全新策略。在生理 pH 值下，肽-铋环瞬间形成，在水溶液中稳定数周，并且比其线性前体更能抵抗蛋白水解。该策略允许对生化筛选测定即时生成双环配体。我们针对寨卡病毒和西尼罗河病毒的蛋白酶进行了两项筛选实验，证明了这一点，揭示了一种新的先导化合物，对两种蛋白酶的抑制常数分别为 23 和 150 nM。双环肽比没有铋的线性类似物分别高 130 倍和 19 倍。
