Faculty of Chemistry, Center for Natural Product Research, University of Havana, Cuba.
Department of Pharmacy, Drug Design group, University of, Groningen, The Netherlands.
Angew Chem Int Ed Engl. 2020 Mar 23;59(13):5235-5241. doi: 10.1002/anie.201916257. Epub 2020 Feb 6.
Stapled peptides are chemical entities in-between biologics and small molecules, which have proven to be the solution to high affinity protein-protein interaction antagonism, while keeping control over pharmacological performance such as stability and membrane penetration. We demonstrate that the multicomponent reaction-based stapling is an effective strategy for the development of α-helical peptides with highly potent dual antagonistic action of MDM2 and MDMX binding p53. Such a potent inhibitory activity of p53-MDM2/X interactions was assessed by fluorescence polarization, microscale thermophoresis, and 2D NMR, while several cocrystal structures with MDM2 were obtained. This MCR stapling protocol proved efficient and versatile in terms of diversity generation at the staple, as evidenced by the incorporation of both exo- and endo-cyclic hydrophobic moieties at the side chain cross-linkers. The interaction of the Ugi-staple fragments with the target protein was demonstrated by crystallography.
订书肽是介于生物制剂和小分子之间的化学实体，已被证明是解决高亲和力蛋白-蛋白相互作用拮抗作用的有效方法，同时还能控制药理学性能，如稳定性和膜穿透性。我们证明了基于多组分反应的订书肽是一种有效的策略，可用于开发具有高度有效双重拮抗作用的α-螺旋肽，该肽能结合 MDM2 和 MDMX 来抑制 p53。通过荧光偏振、微量热泳动和二维 NMR 评估了 p53-MDM2/X 相互作用的这种强抑制活性，同时还获得了与 MDM2 的几个共晶结构。该 MCR 订书肽方案在订书肽多样性生成方面表现出高效和多功能性，这可通过在侧链交联剂中引入内外环疏水性部分来证明。通过晶体学证明了 Ugi-订书肽片段与靶蛋白的相互作用。
