European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-09-11 , DOI: 10.1016/j.ejmech.2020.112814 Paulina Fortuna , Aleksandra Twarda-Clapa , Lukasz Skalniak , Katarzyna Ożga , Tad A. Holak , Łukasz Berlicki
A ‘foldamerization’ strategy for the discovery of biologically active peptide is evaluated using as an example the peptides that inhibit the p53-MDM2/X interactions. Application of a peptide scan with two constrained β-residue of trans and cis stereochemistry indicated a substitution pattern that leads to active molecules with enhanced conformational stability and high resistance to proteolysis. This procedure led to the discovery of a peptide that showed subnanomolar inhibition of the p53-MDM2 interaction (Ki = 0.4 nM) with resistance to proteolysis enhanced by ca. two orders of magnitude. Crystallographic analysis and molecular modelling allowed for understanding of these peptide-protein interactions at the molecular level.
中文翻译:
通过掺入反式或顺式-2-氨基环戊烷羧酸残基来抑制p53-MDM2 / X相互作用的肽的系统性“折叠化”
以抑制p53-MDM2 / X相互作用的肽为例,评估了发现生物活性肽的“折叠化”策略。用的两个受约束β-残基的肽扫描中的应用反式和顺式立体化学表示的取代模式,导致具有增强的构象稳定性和对蛋白酶解的抗性高活性分子。该程序导致发现了一种肽,该肽显示出对p53-MDM2相互作用的亚纳摩尔抑制(K i = 0.4 nM),并且对蛋白水解的抵抗力大约为。两个数量级。晶体学分析和分子建模使得可以在分子水平上理解这些肽-蛋白质相互作用。