TAT-cyclo-CLLFVY is a selective HIF-1 dimerization inhibitor that blocks the protein-protein interaction between recombinant His-HIF-1α and GST-HIF-1β (IC50 = 1.3 μM). Notably, it does not affect the interaction of His-HIF-2α with GST-HIF-1β. In vitro studies demonstrate that TAT-cyclo-CLLFVY suppresses hypoxia-induced HIF-1 activity, leading to reduced expression of VEGF and CAIX in osteosarcoma and breast cancer cells lines, and it reduces the tubulization of hypoxic HUVECs.

TAT-cyclo-CLLFVY Disrupts HIF-1 Dimerization in MCF-7 and U2OS Cells. An in situ proximity ligation assay (PLA) was employed to directly investigate the impact of TAT-cyclo-CLLFVY on the endogenous interaction between HIF-1α and HIF-1β within intact cells. TAT-cyclo-CLLFVY inhibits HIF-1-mediated cellular hypoxia response. The effect of TAT-cyclo-CLLFVY's destruction of HIF-1α/HIF-1β heterodimer on cell hypoxia response was characterized. A quantitative immunoassay assessed the impact TAT-cyclo-CLLFVY's on vascular endothelial growth factor (VEGF), an HIF-1 regulatory gene that stimulates angiogenesis under hypoxic conditions. Luciferase reporter assay showed that TAT-cyclo-CLLFVY had no impact on luciferase signals in either MCF-7 or U2OS cells. While it did not interfere with HIF-2-mediated hypoxia responses, it effectively suppressed HIF-1 activity within the cells.

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Synthesis of TAT-cyclo-CLLFVY



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White lyophilized solid

Reference Reading:

1. A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells

Miranda, E., Nordgren, I.K., Male, A.L., Lawrence, C.E., Hoakwie, F., Cuda, F., Court, W., Fox, K.R., Townsend, P.A., Packham, G.K. and Eccles, S.A., 2013. Journal of the American Chemical Society, 135(28), pp.10418-10425.

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.

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