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. Author manuscript; available in PMC: 2018 Dec 1.
Published in final edited form as: Bioorg Med Chem Lett. 2017 Oct 21;27(23):5089–5099. doi: 10.1016/j.bmcl.2017.10.051

Figure 7.

Figure 7

Structure and in vivo activity of the first cyclotide designed to antagonize an intracellular protein-protein interaction in vivo. A. Solution structure of the engineered cyclotide MCo-PMI (magenta) and its intracellular molecular target, the p53 binding domain of oncogene Hdm2 (blue). The cyclotide binds with low nM affinity to both the p53-binding domains of Hdm2 and HdmX. B. Cyclotide MCo-PMI activates the p53 tumor suppressor pathway and blocks tumor growth in a human colorectal carcinoma xenograft mouse model. HCT116 p53+/+ xenografts mice were treated with vehicle (5% dextrose in water), nutlin 3 (10 mg/kg) or cyclotide (40 mg/kg, 7.6 mmol/kg) by intravenous injection daily for up to 38 days. Tumor volume was monitored by caliper measurement. C. Tumors samples were also subjected to SDS-PAGE and analyzed by western blotting for p53, Hdm2 and p21, indicating activation of p53 on tumor tissue.