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Chemical biological studies for the development of drug seeds for Parkinson's disease (本文)

片浦, 哲志 慶應義塾大学

2020.06.10

概要

Chemical biology is an interdisciplinary study done at the interface of chemistry and biology. In this area, small molecules produced by organic and synthetic chemistry or harvested from natural resources such as secondary metabolites from microbial origin are utilized as chemical probes to understand the molecular mechanisms underlying biological events. Chemical genetics is a part of chemical biology and has a root in genetics (Figure 1-1). Classical genetics is achieved by screening of genes that have random mutation and by isolation of mutant individuals that are responsible for a phenotype of interest (forward genetics). On the other hand, functional analysis of a specific gene against a phenotype by using gene modification including deletion, silencing, and point mutation is called reverse genetics. Similarly, chemical genetics is consisted of forward chemical genetics and reverse chemical genetics. In forward chemical genetics, bioactive small molecules that modulate an interested phenotype are screened from chemical library, and then the hit compounds are used as bioprobes to identify the target proteins and signal transduction pathways that are responsible for the phenotype. In reverse chemical genetics, small molecules that interact with a specific protein of interest are screened from chemical library and modified through synthetic chemistry, and then the function of protein is analyzed by the effect on the phenotype using the chemicals. So far, chemical genetics has been revealed a wide variety of molecular mechanisms. For example, identification of FK506 binding protein, calcineurin, by using FK506 that inhibits T lymphocyte signal transduction, revealed not only the mechanism of action of FK506 but also how T cells- mediated immunity is regulated [1]. Moreover, chemical genetics approach is also compatible with drug discovery research because it is necessary for novel drugs to be elucidated their mechanisms of action, providing us to use for disease-modifying therapy and to predict and take measure to side effects of the drugs [2].

Chemical genomics is a systematic and integrated chemical genetics-approach based on functional genomics. For this, chemical libraries consisted of small molecules that are target-identified (have well-established modes of action) are used for screening. Target information of the hit compounds from screening can be used to i) identify the diverse biological pathways; ii) novel drug targets; iii) predict the modes of action of uncharacterized compounds. For example, chemical genomics was applied to reveal that target of rapamycin (TOR) has a diverse biological activity such as nutrient sensing, regulation of transcription, autophagy, ubiquitin-dependent proteasomal degradation, and microtubule related function in Saccharomyces cerevisiae [3]. Second example is the application to cancer research, which indicated that the inhibition of heat shock protein 90 (HSP90) could be a novel therapeutic strategy [4]. Thus, chemical biology including chemical genetics and chemical genomics plays a critical role in biological research and drug discovery.

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