TY - JOUR
T1 - Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor
AU - Sakai, Katsuya
AU - Passioura, Toby
AU - Sato, Hiroki
AU - Ito, Kenichiro
AU - Furuhashi, Hiroki
AU - Umitsu, Masataka
AU - Takagi, Junichi
AU - Kato, Yukinari
AU - Mukai, Hidefumi
AU - Warashina, Shota
AU - Zouda, Maki
AU - Watanabe, Yasuyoshi
AU - Yano, Seiji
AU - Shibata, Mikihiro
AU - Suga, Hiroaki
AU - Matsumoto, Kunio
N1 - Funding Information:
This work was supported by World Premier International Research Center Initiative (WPI), MEXT, Japan. This work was supported in part by the A-STEP (Adaptable and Seamless Technology Transfer Program through Target-driven R&D) (grant no. AS262Z) from the Japan Science and Technology Agency (JST), the Medical Research Fund of Takeda Science Foundation, the Mitani Foundation for Research and Development, the Grant-in-Aid for JSPS Scientific Research (C) (no. 16K08544) to K.S., a Grant-in-Aid for JSPS Scientific Research (B) (no. 15K14473) to K.M., Project for Cancer Research and Therapeutic Evolution (P-CREATE) from the Japan Agency for Medical Research and development (AMED) to Y.W., H.M., K.M. and T.P., Basic Science and Platform Technology Program for Innovative Biological Medicine from AMED to H. Suga, a Grant-in-Aid for JSPS Research Activity Start-up (no. 16H06830) to H. Sato, a Grant-in-Aid for JSPS Fellows (no. 23-7727) to K.I., a Grant-in-Aid for JSPS Scientific Research (B) (no. 18K01836) to M.S. This work was performed under the Cooperative Research Program of the Institute for Protein Research, Osaka University (no. CR15-05) and an Extramural Collaborative Research Grant from the Cancer Research Institute (Kanazawa University). We thank T. Ando (Kanazawa University) for providing HS-AFM apparatus, T. Uchihashi (Nagoya University) for providing the analytical software of HS-AFM, Y. Kanayama and R. Zochi for their assistance in 64Cu production, Y. Wada and E. Hayashinaka for their assistance in reconstructing the PET images and Enago (www.enago.jp) for the English language review.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41589-019-0285-7
DO - 10.1038/s41589-019-0285-7
M3 - Article
C2 - 31101918
AN - SCOPUS:85065793461
SN - 1552-4450
VL - 15
SP - 598
EP - 606
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 6
ER -
