Chemical Biology is focused on elucidating the mechanism and network of biological reactions by using chemical compounds.  Identification of target proteins for chemical compounds gives us a valuable information about biological and biochemical reactions, and also a new insight for developing therapeutic agents by analysis of structure-activity relationship.  Thus, Chemical Biology contains both aspects of basic science and expandability into practical use, and is considered as a noteworthy field from all over the world.  The concept of Chemical Genetics aims to reveal a specific function of target protein by using chemical compounds.  For analyzing the function of target proteins, it has been used methods of genetic analysis, such as a target gene disruption or a knockdown by RNA interference, but these methods inhibit all of the function of target proteins.  On the other hand, several chemical compounds show the specific inhibition or activation against target proteins, mediated by a specific binding to the functional domain of proteins. By using these compounds, it is possible to analyze the function of target proteins, more precisely.  Therefore, Chemical Genetics is considered as an innovation exceeded from usual genetics. Taken together, the analysis of Chemical Biology/Chemical Genetics is expected for beneficial contribution to our society, because investigation of novel molecular mechanisms of biological reactions, based on chemical compounds, leads to contribute not only to advance in basic life science, but also to develop the novel therapeutic agents, validations of drugs and personalized medicines.

We have studied about Chemical Biology since 1995, when we started to work about a transcriptional inhibition of an adenosine analogue, DRB, which is a potent protein kinase inhibitor.  In the beginning, we tried to purify the DNA-binding transcription factors, ATF/CREB family proteins, by using DNA-affinity latex beads from HeLa cells nuclear extracts.  Interestingly, we found that the affinity-purified fraction contained ATF/CREB and also kinase activity against ATF/CREB, followed by identifying this kinase.  This finding gave us a great chance for developing our subsequent works, because DRB selectively inhibited this kinase activity.  We expected that the co-purified kinase affected the transcriptional reaction.  Then, we have started to work about the mechanism of transcriptional inhibition by DRB, because there were several reports that DRB inhibits a transcriptional reaction by a specific inhibition of the kinase activity.  Finally, we had succeeded in elucidating a novel mechanism about RNA polymerase II-mediated transcriptional elongation reaction.  In these processes, we could identify the novel protein complexes (DSIF and NELF) related to the DRB-mediated transcriptional inhibition, and revealed the function about these proteins.  These results are accepted internationally with highly evaluation, and both of DSIF and NELF are described in “Molecular Biology of the Cell”, an excellent text book in United States. (As regards these in detail, see the Section of Gene Expression).  Through our study about DRB, we have believed that it would be most valuable field such as the research about the small-molecule-based analysis of biology.

For analysis of Chemical Biology, most important point is how can conveniently identify the target molecules for chemical compounds.  We have developed an application for high performance affinity latex beads, which enable rapid and efficient purification of target proteins for a wide range of chemical compounds from protein library such as cellular extracts (See the section of Functional Magnetic Nano-Particles, and reffered to “Everything of Nano affinity beads” Hiroshi Handa and Haruma Kawaguchi. ; Hiramoto et al., Methods Enzymol., 2002 ).  On the basis of our purification technology, we have succeeded to purify various target proteins for drugs such as immunosuppressors, antibiotics, and agents for anti-cancer or anti-inflammation (Shimizu et al.,Nat Biotechnol., 2000 ; Tomohiro et al., Bioconjug Chem., 2002 ; Nishi et al., J. Biol. Chem., 2003 ; Hatori et al., J Antibiot., 2004 ; Kusunoki et al., J. Pharmcol. Exp., 2005).  In addition, we are now analysing about a wide variety of chemical compounds, such as therapeutic agents (e. g., drugs for chemotherapy, anti-inflammation, anti-rheumatism, anti-osteoporosis, anti-diabetes, analgesia and immunosuppression), endocrine disrupters, nutrients (amino acids and vitamins) and porphyrins (heme).  We have identified their target proteins, and analyzed their mechanisms of action.  Identification of target proteins for chemical compounds helps us to understand the mechanism and network of biological reactions.  We will gradually publish our studies about chemical compounds.  In addition, we have also revealed novel functions about replication protein of adeno-associated virus (AAV) or toxic protein of pathogenic bacteria O157, by identifying their interacting proteins using our affinity beads (Han et al., Virology., 2004).  Now, we attempt to develop applications based on the information about interaction with their target proteins, e. g., DNA recombination systems by replication protein, and systems for diagnosis, prevention and therapy against pathogenic disease.  We are performing our research activity toward development for drug discovery, based on our information about interactions between chemical compounds and target proteins.  As a part of this, we have developed the drug screening system, which can get the hit-compounds interacting with target proteins (or fuctional domains of target proteins) from chemical libraries or mycobacterial extracts (Ohtsu et al., Anal Biochem., 2005).  Furthermore, we attempt to develop the drugs for next-generation and the personalized medicines, by performing the multidisciplinary collaborations with several companies, clinicians, chemists and informatics (Zenkoh et al., Org Lett., 2004).

Regarding Chemical Biology, please see “Chemical Biology & Chemical Genomics (written and edited by Hiroshi Handa)” published from Springer Verlag Tokyo in 2005.  The book provides an outline and the current information about Chemical Biology.