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. 2022 Sep 29;27(19):6430. doi: 10.3390/molecules27196430

Figure 5.

Figure 5

Structure and in vivo activity of an MCoTI-based cyclotide designed to antagonize an intracellular PPI [5]. (A) The structure of the bioactive cyclotide MCo-PMI (magenta) and its intracellular molecular target, the p53 binding domain of oncogene Hdm2 (blue), was determined in solution by NMR. Cyclotide MCo-PMI binds with low nM affinity to 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+/+ mouse xenograft models 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) Tumor samples were also subjected to SDS-PAGE and analyzed by western blotting for p53, Hdm2, and p21, indicating activation of p53 on tumor tissue in vivo. Figure adapted from reference [5].