Chemical Biology Helps Transform the Research Model of New Drugs

Chemical Biology Helps Transform the Research Model of New Drugs

March 06, 2017 Source: Chinese Journal of Science

"Study on Signal Transduction Process Based on Chemical Small Molecule Probes" Major Research Program (hereinafter referred to as "Major Plan") is the first major project initiated by the National Natural Science Foundation of China during the "Eleventh Five-Year Plan" period, and is also a chemical biology The first major project in the field.

Under the active guidance of this major program, the researchers closely integrated the basic research of small molecule regulation signal transduction process with innovative drug discovery, and fully utilized the concepts and techniques of chemical biology in the confirmation of target pharmacology function, and found some high quality. New targets and novel lead compounds. "These initiatives and achievements have really promoted the establishment and development of China's 'based on new research in chemical biology' model." Zhang Lihe, the leader of the major program expert group and academician of the Chinese Academy of Sciences, said.

Complete "innovation chain"

In the past, it was a common phenomenon that new drug research and development focused more on applied research and insufficient use of basic biological research. Under the guidance of the "Major Plan", the Shanghai Institute of Materia Medica, Chinese Academy of Sciences (hereinafter referred to as "Shanghai Pharmaceutical Institute") has been conducting research on key scientific issues such as new targets, biomarkers and lead compounds in eight years of research. The research has improved the "all-innovation chain" of drug research and development from scientific theory to basic research output, patent application and drug development, and technology transfer.

A new case study of the old drug naftifine hydrochloride is a typical case. Since 2012, Shanghai Institute of Pharmaceutical Research, Lan Lefu, Yang Caiguang, and Jiang Hualiang have collaborated with Li Jian, a professor at East China University of Science and Technology, to discover new types of antibacterial drugs through the mechanism of "antibacterial and non-bacterial".

"This type of antibacterial new drug called 'anti-virulence drug' has a different mechanism of action than traditional antibiotics, and aims to achieve antibacterial treatment by blocking the pathogenic part of the bacteria instead of directly killing the bacteria or inhibiting the growth of the bacteria. "The researchers explained to the reporter of the Chinese Journal of Science and Technology, "This new antibacterial idea that jumps out of traditional antibiotics is an attempt to actively face the challenge of global antibiotic resistance."

Under the support of the "Major Program", the researchers carried out basic research on the precise regulation of bacterial pathogenicity signal transduction process by small chemical molecules, and actively explored the feasibility of using small molecule compounds to intervene in pathogenicity. They found that transpeptidase small molecule inhibitors did not affect bacterial growth, but effectively prolonged the survival of resistant S. aureus-infected mice. Naftifine significantly reduces the production of golden yellow pigment by inhibiting the function of the nodulin CrtN in the S. aureus golden yellow pigment biosynthesis pathway, thereby greatly limiting the infection-causing ability of S. aureus. At present, this compound patent has been transferred to Hubei Biomedical Industry Technology Research Institute Co., Ltd. for further development.

Foundation and application at the same time

The epigenetic signal transduction pathway is an emerging frontier in the international discovery of drug targets and the discovery of original innovative drugs. According to the researchers, the development of new drugs usually lags far behind the basic research of biology, and the development of new drugs based on epigenetic signal transduction pathways is expected to go hand in hand with basic biology research.

Scientists have learned that methylation (referred to as "m6A") modification at the sixth nitrogen atom of the messenger RNA molecule adenine is the most common RNA methylation modification, while messenger RNA methylation modification disorder and metabolic disease Such major diseases are closely related. Yang Caiguang cooperated with Luo Cheng and Jiang Hualiang to study the structure and mechanism of the modified base of m6A demethylase FTO to carry out small molecule regulation research, and found that the natural product rhein can inhibit the demethylation function of FTO and effectively intervene. Modification abundance of m6A on intracellular messenger RNA.

The researchers also identified a selective small molecule inhibitor targeting FTO, the non-steroidal anti-inflammatory drug, meclofenamic acid, by designing a high-throughput screening protocol. Yang Caiguang's research group cooperated with Zhou Xiang's research group of Wuhan University to successfully use the chemical probe to realize the "visualization" of FTO protein, which provided a better probe molecule for further study of the molecular mechanism of FTO.

These subjects use chemical probes to study the dynamic modification of m6A on the regulation of messenger RNA, and have carried out reliable target confirmation studies for drug discovery in diseases such as tumors and metabolic disorders. "Currently, in this field, the discovery of new drugs and basic research will simultaneously add new impetus to the original innovative drug research and development." Researchers expect.

Aiming at more challenging frontiers

At present, many new drug developers are not satisfied with the confirmation of known targets, and the more challenging frontier has become the focus of researchers in this field. Among them, the precise intervention of "protein-protein interaction" is regarded as the next "gold mine" discovered by new drugs.

Jiang Hualiang and He Chuan, a professor at the University of Chicago, are aiming at this frontier. They conducted chemical biology studies on the targetability of copper ion chaperone proteins. According to Jiang Hualiang, the researchers used a computational drug design to screen out a number of compounds that bind to the copper transporter interface of two copper chaperones, Atox1 and CCS, and showed excellent antitumor efficacy. At the same time, Jiang Hualiang and Yang Caiguang collaborated with Liu Jiang, a researcher at the Beijing Genomics Institute, to discover SPOP inhibitors that disrupt the interaction of two key proteins, SPOP and PTEN, in the pathogenesis of clear cell renal cell carcinoma.

Scientists have also discovered new targets and drug candidates for anti-inflammatory drugs around the regulatory mechanisms and signaling pathways of protein interactions. For example, Wu Qiao's group of Xiamen University used small molecule compounds to interfere with protein interactions on the p38 kinase pathway, and played a more effective role in inhibiting inflammation, providing new targets and new ideas for the development of anti-inflammatory drugs.

Experts believe that these studies not only provide small molecular compound tools for basic biological research such as tumors and inflammation, but also promote the discovery of innovative drugs in the field of disease treatment.

In addition, Xu Qiang of Nanjing University found that andrographolide can reduce colitis and ultimately inhibit colon cancer by inducing mitochondrial autophagy in macrophages, and one of the compounds has entered clinical trials. Tsinghua University Liu Gang's project has been combined into a natural tumor drug paclitaxel and muramyl dipeptide mimics (MTC-220), which can synergistically inhibit inflammatory cytokines in the tumor microenvironment, thereby inhibiting tumor metastasis and tumor growth. The compound is being submitted for clinical trials.

In the view of scientists participating in major programs, the major program has achieved fruitful functional and functional research and validation, obtained new candidate targets with independent intellectual property rights and lead compounds of novel structures, and developed "chemical biology-based The new model of new drug research fully demonstrates the important position and prospects of chemical biology models in innovative drug research.

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