School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
Chemistry, R&D Oncology, AstraZeneca, Cambridge, CB4 0QA, UK.
Angew Chem Int Ed Engl. 2023 Jun 5;62(23):e202301209. doi: 10.1002/anie.202301209. Epub 2023 May 2.
With over 60 % of protein-protein interfaces featuring an α-helix, the use of α-helix mimetics as inhibitors of these interactions is a prevalent therapeutic strategy. However, methods to control the conformation of mimetics, thus enabling maximum efficacy, can be restrictive. Alternatively, conformation can be controlled through the introduction of destabilizing syn-pentane interactions. This tactic, which is often adopted by Nature, is not a common feature of lead optimization owing to the significant synthetic effort required. Through assembly-line synthesis with NMR and computational analysis, we have shown that alternating syn-anti configured contiguously substituted hydrocarbons, by avoiding syn-pentane interactions, adopt well-defined conformations that present functional groups in an arrangement that mimics the α-helix. The design of a p53 mimetic that binds to Mdm2 with moderate to good affinity, demonstrates the therapeutic promise of these scaffolds.
超过 60%的蛋白质-蛋白质界面具有α-螺旋结构，因此使用α-螺旋类似物作为这些相互作用的抑制剂是一种常见的治疗策略。然而，控制类似物构象的方法，从而实现最大疗效，可能会受到限制。或者，可以通过引入不稳定的顺式戊烷相互作用来控制构象。这种策略通常被自然界采用，但由于需要大量的合成工作，因此不是先导优化的常见特征。通过使用 NMR 和计算分析的流水线合成，我们已经表明，通过连续取代的烃类化合物的交替顺式-反式构型，避免顺式戊烷相互作用，采用了明确的构象，这些构象呈现出的官能团排列方式类似于α-螺旋。与 Mdm2 具有中等至良好亲和力的 p53 类似物的设计证明了这些支架的治疗潜力。
