Overexpressed pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-X_L can render tumor cells malignant. Leukemia drug venetoclax is currently the only approved selective BCL-2 inhibitor. However, its application has led to an emergence of resistant mutations, calling for drugs with an innovative mechanism of action. Herein we present cyclic peptides (CPs) with nanomolar-level binding affinities to BCL-2 or BCL-X_L, and further reveal the structural and functional mechanisms of how these CPs target two proteins in a fashion that is remarkably different from traditional small-molecule inhibitors. In addition, these CPs can bind to the venetoclax-resistant clinical BCL-2 mutants with similar affinities as to the wild-type protein. Furthermore, we identify a single-residue discrepancy between BCL-2 D111 and BCL-X_L A104 as a molecular “switch” that can differently engage CPs. Our study suggests that CPs may inhibit BCL-2 or BCL-X_L by delicately modulating protein-protein interactions, potentially benefiting the development of next-generation therapeutics.

过度表达的促生存 B 细胞淋巴瘤 2 (BCL-2) 家族蛋白 BCL-2 和 BCL-X _L可使肿瘤细胞恶性。白血病药物venetoclax是目前唯一获批的选择性BCL-2抑制剂。然而，它的应用导致了耐药突变的出现，需要具有创新作用机制的药物。在此，我们提出了与 BCL-2 或 BCL- _XL具有纳摩尔水平结合亲和力的环肽（CP），并进一步揭示了这些 CP 如何以与传统小分子显着不同的方式靶向两种蛋白质的结构和功能机制。分子抑制剂。此外，这些 CP 可以与 Venetoclax 耐药的临床 BCL-2 突变体结合，并具有与野生型蛋白相似的亲和力。此外，我们发现 BCL-2 D111 和 BCL-X _L A104 之间的单一残基差异是可以以不同方式与 CP 结合的分子“开关”。我们的研究表明，CP 可能通过微妙地调节蛋白质-蛋白质相互作用来抑制 BCL-2 或 BCL- _XL ，这可能有利于下一代疗法的开发。