KANAZAWA, Japan, June 5, 2019 /PRNewswire/ -- Researchers at Kanazawa University report in Nature Chemical Biology the identification of a molecule capable of inhibiting cell growth in cancer microenvironment. The discovery is relevant for diagnostic tumor imaging and could also contribute to the development of cancer treatment.
One of the processes involved in the progression of cancer is the activation of a molecule known as hepatocyte growth factor (HGF). Normally, HGF is a passive molecule, occurring in blood and tissue; it consists of a single chain (scHGF) of polypeptides. In a cancer microenvironment, however, a cleavage of scHGF happens, resulting in a two-chain structure (tcHGF), which makes the molecule active: tcHGF triggers a signaling pathway causing the growth of cells. Detecting active HGF is important for diagnosing and treating cancer. Now, an interdisciplinary team of researchers, including Kunio Matsumoto, Katsuya Sakai and Mikihiro Shibata at the WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Hiroaki Suga at the Department of Chemistry, Graduate School of Science, The University of Tokyo, Hidefumi Mukai and Yasuyoshi Watanabe at RIKEN Center for Biosystems Dynamics Research and colleagues have identified a molecule, called HiP-8, that can selectively recognize tcHGF. Moreover, HiP-8 binding to tcHGF hinders the latter's signaling activity, inhibiting the proliferation of cancer cells.
In trying to find candidate molecules that can inhibit active HGF, the researchers looked within the class of macrocyclic peptides — molecules nowadays extensively researched as candidates for drugs targeting protein–protein interactions involved in biochemical signaling pathways. Using the outstanding technology known as the 'RaPID system' that rapidly screens the diverse maclocyclic library (1012 – 1014 diversity), Matsumoto and colleagues arrived at a shortlist of 16 candidate 'HGF-inhibitory peptides' (HiPs) that they then synthesized and tested.
HiP-8 was found to have the best properties. In in vitro experiments, HiP-8 potently inhibited the cellular response in tumor cells induced by HGF. It was also successfully tested that HiP-8 does not inhibit other pathways — in other words, that the molecule only targets tcHGF. The scientists were able to describe the precise structural difference between sc- and tcHGF, and discovered that the inhibition by HiP-8 of the latter is allosteric (meaning that HiP-8 binds to tcHGF at a site that is not the active one). By using high-speed atomic force microscopy, they observed a movie for dynamic change of molecular shape, before and after HiP-8 binding to HGF. The molecular shape of HGF was dynamically changing, but it was suppressed after HiP-8 binding. A small molecule inhibits dynamic movement of a large molecule, like 'static inhibition'.
The researchers also investigated the effect of administering HiP-8 intravenously in a mouse model, to check its potential as a PET (positron-emission tomography) imaging probe. Good, non-invasive visualization of the mouse tumor was obtained in this way.
The work of Matsumoto and colleagues shows, with HiP-8 in the context of tcHGF as an example, the unique binding properties achievable with macrocyclic peptides. Quoting the researchers: "This [inhibiting] binding property of macrocyclic peptides and their advantages in imaging applications present considerable diagnostic and therapeutic development potential."
Macrocyclic peptides are molecules featuring peptides in a ring structure; a peptide is a biomolecule consisting of a chain of amino acids. Macrocyclic peptides form a large family of compounds and are found in many organisms, including bacteria, plants and mammals. Nowadays, the molecules are intensively researched as drug candidates because of suitable properties including synthetic accessibility and specific binding capabilities — especially binding to protein surfaces. Hiroaki Suga from University of Tokyo established the innovative technology known as the Random Peptide Integrative Discovery (RaPID) () system' which efficiently enables screening and discovery of macrocyclic peptides that bind to target protein. Kunio Matsumoto from Kanazawa University, Hiroaki Suga, and colleagues have now used RaPID screening to identify macrocyclic peptides capable of inhibiting the action of hepatocyte growth factor (HGF), a molecule involved in cancer progression. They found a series of HGF inhibitory peptides (HiPs), of which one, HiP-8, displays potent inhibition and can be used for the non-invasive visualization of tumors.
Positron-emission tomography (PET) is a technique used in nuclear medicine for visualizing biological processes in the body. The working principle is that of pairs of gamma rays being (indirectly) emitted by a so-called radioligand, which emits positrons (a positron is an electron-like, but positively charged, particle). The radioligand is attached to a biologically active molecule (called the radioactive tracer). Matsumoto and colleagues applied PET with HiP-8 as the radioactive tracer, enabling the non-invasive visualization, and inhibition, of HGF.
Katsuya Sakai, Toby Passioura, Hiroki Sato, Kenichiro Ito, Hiroki Furuhashi, Masataka Umitsu, Junichi Takagi, Yukinari Kato, Hidefumi Mukai, Shota Warashina, Maki Zouda, Yasuyoshi Watanabe, Seiji Yano, Mikihiro Shibata, Hiroaki Suga, and Kunio Matsumoto. Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor, Nature Chemical Biology 15, 598−606 (2019).
Positron-emission tomography (PET) images of mice bearing tumor, using HiP-8 as the radioactive tracer.
About Kanazawa University
As the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities.
The University is located on the coast of the Sea of Japan in Kanazawa – a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students including 600 from overseas.
Kanazawa University website: http://www.kanazawa-u.ac.jp/e/
Kakuma, Kanazawa, Ishikawa 920-1192, JAPAN
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