Research Project
Grant-in-Aid for Scientific Research (B)
Family S46 peptidases are widely distributed in anaerobic Gram-negative species in the genera Bacteroides, Parabacteroides, and Porphyromonas, but they are not found in mammals. Therefore, S46 peptidases are ideal targets for novel antibiotics. We determined a crystal structure of dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) in complex with citrate ions at a 1.50 Å resolution using a high-quality space-grown crystal. The bound citrate ion, a potassium ion, and a water molecule in the active site of PgDPP11 were regarded to mimic the binding of an acidic amino acid and were utilized as a pharmacophore for an in silico inhibitor screening. The screening resulted in the first nonpeptidyl inhibitor of S46 peptidases, SH-5. The binding mode of SH-5 was confirmed by crystal structure analysis at a 2.39 Å resolution. The hit compound SH-5 and a related compound represent promising lead structures for further rational design of potent inhibitors against PgDPP11.
歯周病原因菌Porphyromonas gingivalisや多剤耐性菌Stenotrophomonas maltophiliaは糖ではなく蛋白質やペプチドをエネルギー源とする「糖非発酵性細菌」である。従って、これらの菌のペプチド代謝経路を阻害するような化合物は新規抗生物質と成り得る。従って、本研究の学術的意義は、糖非発酵性細菌を標的とした新規抗生物質開発に繋がるものである。また、本研究の社会的意義として、製薬企業は感染症関連研究に対して消極的なため大学研究者による抗生物質開発に繋がる基盤研究は社会的に極めて重要であることを強調したい。
All 2019 2018 2017 2016 Other
All Journal Article (6 results) (of which Int'l Joint Research: 1 results, Peer Reviewed: 6 results, Open Access: 4 results, Acknowledgement Compliant: 1 results) Presentation (24 results) (of which Int'l Joint Research: 15 results) Remarks (1 results)
International journal of microgravity science and application
Volume: 36 Issue: 1 Pages: 360106
10.15011//jasma.36.360106
130007842629
Scientific Reports
Volume: 8 Issue: 1 Pages: 2714-2714
10.1038/s41598-018-21056-y
SAR News
Volume: 32 Pages: 10-18
Acta Crystallographica Section F
Volume: 73 Issue: 11 Pages: 501-606
10.1107/s2053230x17014911
日本結晶学会誌
Volume: 58 Pages: 221-227
130005267922
Photon Factory Highlights 2015
Volume: - Pages: 56-57
http://iss.jaxa.jp/topics/2016/07/160715.html