Professor Deng Xuming’s research team has made breakthroughs in the research of type II ribosomal inactivating proteins (RIPs II) inhibitors. After years of hard work, researchers have discovered that baicalin, a traditional Chinese medicine component, is a specific inhibitor of RIPs II, and revealed a new mechanism for baicalin to inhibit RIPs II. This research was funded by the National Key Basic Research and Development Program (Project No.: 2013CB127205) and the National Key Natural Science Foundation (Project No. 31130053).
RIPs II are a class of highly toxic toxins that can cause cell protein translation to stop and cause cell death, including ricin, Shiga-like toxin secreted by enterohemorrhagic Escherichia coli O157:H7, and porcine edema virus. As RIPs II are closely related to biosafety and major infectious diseases, the exploration of RIPs II detoxification drugs has always been an international research hot topic. At present, there are many reports on RIPs II inhibitors, but a small molecule compound has not been found to have a definite therapeutic effect on poisoned animal models. Although the research on toxin neutralizing antibodies has made some progress, due to the experimental therapeutic effect and manufacturing cost, its limitations hinder its clinical application and face the challenge of potential toxin diversity identification.
The research group has carried out long-term research on screening RIPs II inhibitors from natural compounds and found that baicalin, a traditional Chinese medicine component, can inhibit the biological activities of ricin and Shiga toxin type II in vitro, and significantly improve the survival rate of infected mice. In order to reveal its mechanism of action, the research team worked with Rao Zihe of the Institute of Biophysics of the Chinese Academy of Sciences to analyze the crystal structure of the ricin toxin A subunit-baicalin complex with a resolution of 2.2 Å. Unlike small molecule inhibitors that directly target the active center of a protein, baicalin can induce ricin to form a "tandem" polymer, which prevents the active center from being exposed (see Figure 1), thereby inhibiting the biology of the toxin Activity, and analysis and verification of the corresponding binding site.
The research group further studied the therapeutic effect of baicalin on O157:H7 infected mice by establishing an animal model of enterohemorrhagic E. coli infection, and found that baicalin has an effective therapeutic effect on infected mice, with a protection rate of up to 80%, challenge control All groups died; the results suggest that baicalin can be used as a drug candidate for the treatment of human enterohemorrhagic Escherichia coli (O157:H7 and O104:H4, etc.) infections. Based on this result, the research team has now cooperated with Tianjin International Biomedical Research Institute to jointly develop baicalin as a new drug for the treatment of enterohemorrhagic E. coli infection.
The research results were successively published in J Biol Chem. 2015 May 15;290(20):12899-907, Antimicrob Agents Chemother. 2015 Nov;59(11):7054-60 and Front Microbiol. 2017 Mar 9;8:395; The Chem. Res. Toxicol magazine under the American Chemical Society (ACS) reported and evaluated the research in the form of Spotlight. In addition, related research has obtained 2 national invention patents (ZL201410066491.X and ZL201410166500.2).