Rapid Identification via In Situ Click Chemistry of a Novel Chitinase Inhibitor
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- Hirose Tomoyasu
- Kitasato Institute for Life Sciences, Kitasato University Graduate School of Infection Control Sciences, Kitasato University
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- Sunazuka Toshiaki
- Kitasato Institute for Life Sciences, Kitasato University Graduate School of Infection Control Sciences, Kitasato University
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- Ōmura Satoshi
- Kitasato Institute for Life Sciences, Kitasato University
書誌事項
- タイトル別名
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- Rapid Identification via <i>In Situ</i> Click Chemistry of a Novel Chitinase Inhibitor
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<p>In situ click chemistry is a target-guided synthesis technique for discovering highly potent enzyme inhibitors by assembling azides and alkynes into triazoles inside the affinity site of a target enzyme. We here review research aimed at the rapid discovery of a novel and potent inhibitor of bacterial chitinases using in situ click chemistry. Chitinase inhibitors have chemotherapeutic potential as fungicides, pesticides and anti-asthmatics. Argifin, which has been isolated and characterized as a cyclopentapeptide natural product by our research group, shows strong inhibitory activity against chitinases. Via a combination of efforts to develop a useful chitinase inhibitor from an azide-bearing argifin fragment and application of the chitinase template in situ click chemistry with a library of alkynes, we rapidly obtained a very potent and novel 1,5-disubstituted triazole inhibitor of Serratia marcescens chitinase (SmChi) B. The new inhibitor expressed a 300-fold increase of inhibition against SmChiB compared to that of argifin. We also succeeded in obtaining crystal structures of a chitinase complexed with an azide inhibitor and an O-allyl oxime fragment as a mimic of a click partner, revealing an elegant mechanism for accelerating syn-triazole formation of ‘in situ click chemistry’, thereby allowing generation of its own distinct inhibitor. This represents the first example of expression of a pre-triazole state of ‘in situ click chemistry’. This work exemplifies the benefits of ‘in situ click chemistry’-approach in efforts to produce novel and reliable inhibitors.</p>
収録刊行物
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- 有機合成化学協会誌
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有機合成化学協会誌 74 (11), 1090-1097, 2016
公益社団法人 有機合成化学協会
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詳細情報 詳細情報について
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- CRID
- 1390001205340048768
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- NII論文ID
- 130005433321
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- NII書誌ID
- AN0024521X
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- ISSN
- 18836526
- 00379980
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- NDL書誌ID
- 027740259
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
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