農学部研究紹介英語版2019-2020
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Laboratory of Drug Target Research Isao KII Associate Professor, Ph.D. Research keywords ・Kinase ・Folding intermediate ・Selectivity of drug ・Drug screening Small molecules in drugs and foods bind to its target proteins in living cells, and activate or inhibit its cellular functions, giving pharmacological effects. However, small molecules often bind to non-target proteins in cells, leading to undesired side effects. To reduce side effects of small molecules in drugs and foods, we need to enhance the target selectivity of the small molecules. In our laboratory, to enhance the target selectivity, we have focused on a transitional state of the drug target protein. It is a folding intermediate. Our goal is to develop the drug development platform that produces small molecule drugs without side effects. (Kii et al. Nature Communications 2016) Integrated Bioscience Division Small molecule kinase inhibitor To enhance target selectivity of kinase inhibitors, we have designed small molecules that selectively bind to its folding process. Target identification of small molecule To identify proteins targeted by small molecule in living cells, we have developed a new system that covers cellular proteome. Development of enhanced Antibody-Drug Conjugates (ADCs) We have developed ADCs that have small molecule drugs with bio-orthogonal chemistry. Folding process polypeptide Mature protein Folding intermediate (Transitional state) NEW Drug Target Old Drug Target Chemical Knockdown Depletion of the target protein in cells through Inhibition of its folding process by small molecule Chemical Biology Innovative collaboration between chemistry and biology (Kii et al. Org Biomol Chem 2010) Chemical Biology Laboratory Junko OHKANDA Professor, Ph.D. Dr. Ohkanda’ s research interests include bioorganic chemistry, medicinal chemistry, supramolecular chemistry, chemical biology, and new strategies in medicinal chemistry. Approaches in the Ohkanda Lab include: •Intracellular generation of agents that disrupt protein interactions. We study a new approach of introducing large molecules by exploiting template synthesis on the targeted protein surfaces. •Design of bivalent inhibitors for simultaneous recognition of pocket and surfaces. By anchoring into a pocket, our strategy aims to deliver a minimally sized inhibitor to a featureless protein interface. •Elucidation of the mechanism of action of natural product-based antitumor agents. We work on chemical transformation of fusicoccins, a phytotoxin, to explore a new series of antitumor agents and to understand how it works in cells. C D Multivalent molecules generated by assembling of small modules are capable of modulation of intracellular protein interactions. Integrated Bioscience Division A B C D A C The Ohkanda Research Lab focuses on the problems that lie at the interface of organic chemistry and biology. We are particularly interested in the field of molecular recognition and its application to structure-based design of pharmaceutical agents and chemical tools that are useful for better understanding important cellular processes. A major recent area of research of the group includes the design of molecules ranging from low-molecular-weight enzyme inhibitors to mid-sized agents capable of recognition of protein interfaces to control protein interactions. Peptides, natural products, heterocycles, and metal complexes are of interest as the building blocks for rational designing of artificial biomolecules. 1

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