Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom.
J Am Chem Soc. 2013 Jul 17;135(28):10418-25. doi: 10.1021/ja402993u. Epub 2013 Jul 9.
Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcription factor that acts as the master regulator of cellular response to reduced oxygen levels, thus playing a key role in the adaptation, survival, and progression of tumors. Here we report cyclo-CLLFVY, identified from a library of 3.2 million cyclic hexapeptides using a genetically encoded high-throughput screening platform, as an inhibitor of the HIF-1α/HIF-1β protein-protein interaction in vitro and in cells. The identified compound inhibits HIF-1 dimerization and transcription activity by binding to the PAS-B domain of HIF-1α, reducing HIF-1-mediated hypoxia response signaling in a variety of cell lines, without affecting the function of the closely related HIF-2 isoform. The reported cyclic peptide demonstrates the utility of our high-throughput screening platform for the identification of protein-protein interaction inhibitors, and forms the starting point for the development of HIF-1 targeted cancer therapeutics.
缺氧诱导因子-1（HIF-1）是一种异二聚体转录因子，作为细胞对低氧水平反应的主要调节剂，因此在肿瘤的适应、存活和进展中发挥关键作用。在这里，我们报告了cyclo-CLLFVY，它是使用基因编码的高通量筛选平台从 320 万个环六肽文库中鉴定出来的，是体外和细胞中 HIF-1α/HIF-1β 蛋白-蛋白相互作用的抑制剂。该鉴定化合物通过与 HIF-1α 的 PAS-B 结构域结合，抑制 HIF-1 二聚化和转录活性，降低各种细胞系中 HIF-1 介导的低氧反应信号，而不影响密切相关的 HIF-2 同工型的功能。所报道的环肽证明了我们的高通量筛选平台在鉴定蛋白-蛋白相互作用抑制剂方面的实用性，并为开发针对 HIF-1 的癌症治疗药物奠定了基础。
