Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor

• Published in: Nature chemical biology Vol. 15; no. 6; pp. 598 - 606
• Main Authors: Sakai, Katsuya, Passioura, Toby, Sato, Hiroki, Ito, Kenichiro, Furuhashi, Hiroki, Umitsu, Masataka, Takagi, Junichi, Kato, Yukinari, Mukai, Hidefumi, Warashina, Shota, Zouda, Maki, Watanabe, Yasuyoshi, Yano, Seiji, Shibata, Mikihiro, Suga, Hiroaki, Matsumoto, Kunio
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.06.2019
• Subjects: Activation; Allosteric properties; Amino acids; Animals; Atomic force microscopy; Biochemical analysis; c-Met protein; Cancer; Domains; Growth factors; Hepatocyte growth factor; Hepatocyte Growth Factor - analysis; Hepatocyte Growth Factor - antagonists & inhibitors; Hepatocyte Growth Factor - metabolism; Hip; Inhibition; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Medical imaging; Mice; Microenvironments; Microscopy; Neoplasms, Experimental - diagnostic imaging; Neoplasms, Experimental - drug therapy; Optical Imaging; Peptides; Peptides - chemistry; Peptides - pharmacology; Positron emission; Positron emission tomography; Proteolysis; Radioactive tracers; Tumors
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-019-0285-7

Activation of hepatocyte growth factor (HGF) by proteolytic processing is triggered in cancer microenvironments, and subsequent signaling through the MET receptor is involved in cancer progression. However, the structure of HGF remains elusive, and few small/medium-sized molecules can modulate HGF. Here, we identified HiP-8, a macrocyclic peptide consisting of 12 amino acids, which selectively recognizes active HGF. Biochemical analysis and real-time single-molecule imaging by high-speed atomic force microscopy demonstrated that HiP-8 restricted the dynamic domains of HGF into static closed conformations, resulting in allosteric inhibition. Positron emission tomography using HiP-8 as a radiotracer enabled noninvasive visualization and simultaneous inhibition of HGF-MET activation status in tumors in a mouse model. Our results illustrate the conformational change in proteolytic activation of HGF and its detection and inhibition by a macrocyclic peptide, which may be useful for diagnosis and treatment of cancers.