title: Creation of Customized Bioactivity within a 14-Membered Macrolide Scaffold: Design, Synthesis, and Biological Evaluation Using a Family-18 Chitinase.
abstract: Argifin, a 17-membered pentapeptide, inhibits chitinase. As argifin has properties that render it unsuitable as a drug development candidate, we devised a mechanism to create the structural component of argifin that bestows the chitinase inhibition and introduce it into a 14-membered macrolide scaffold. Here we describe (1) the designed macrolide, which exhibits ∼200-fold more potent chitinase inhibition than argifin, (2) the binding modes of the macrolide with Serratia marcescens chitinase B, and (3) the computed analysis explaining the reason for derivatives displaying increased inhibition compared to argifin, the macrolide aglycone displaying inhibition in a nanomolar range. This promises a class of chitinase inhibitors with novel skeletons, providing innovative insight for drug design and the use of macrolides as adaptable, flexible templates for use in drug discovery research and development.
authors.affiliation: †The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sugawara
authors.affiliation: ‡Institute for Enzyme Research, University of Tokushima, 3-18-15 Kuramotocho, Tokushima City, Tokushima, 770-8503, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Maita
authors.affiliation: §School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Gouda
authors.affiliation: †The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: †The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Hirose
authors.affiliation: †The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Kimura
authors.affiliation: †The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Saito
authors.affiliation: †The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakano
authors.affiliation: †The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Kasai
authors.affiliation: †The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nakano
authors.affiliation: †The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Kazuro
authors.initials: K
authors.lastname: Shiomi
authors.affiliation: §School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.affiliation: ∥Department of Applied Biological Chemistry, Faculty of Agriculture, Niigata University, 8050 Ikarashi-2, Niigata 950-2181, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: ‡Institute for Enzyme Research, University of Tokushima, 3-18-15 Kuramotocho, Tokushima City, Tokushima, 770-8503, Japan.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: †The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura
authors.affiliation: †The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sunazuka
mesh_terms: D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D002688:Chitinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D016868:Serratia Infections / Q000188:drug therapy / Q000382:microbiology; D012706:Serratia marcescens / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D018942:Macrolides; D010456:Peptides, Cyclic; C413566:argifin; D002688:Chitinases