Design of non-peptide inhibitors based on structure analyses of the protease/inhibitor complex
| Project/Area Number |
25460160
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | Kyoto Pharmaceutical University |
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Principal Investigator |
Akaji Kenichi 京都薬科大学, 薬学部, 教授 (60142296)
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| Co-Investigator(Renkei-kenkyūsha) |
HATTORI Yasunao 京都薬科大学, 薬学部, 助教 (20567028)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | プロテアーゼ / 阻害剤 / 疎水性相互作用 / 複合体構造解析 / 縮環構造 / 創薬科学 / 医薬品化学 / プロテアーゼ阻害剤 / SARS / BACE1 |
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| Outline of Final Research Achievements |
Evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro) was achieved. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site group to the main-chain nitrogen atom of the P2 position via a methylene linker. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CLpro, which confirmed the fused ring structure functions as a novel scaffold for SARS 3CLpro inhibitor.
Hydroxyethylamine (HEA) isostere, as a transition state mimic, was incorporated into macro-cyclic structures connecting the P2 and P4 site of the substrate sequence of BACE1, a key protease for the onset of Alzheimer diseases. Synthesized cyclic inhibitor showed moderate but clear inhibitory activity for BACE1, which confirmed the ring structure functions as a novel scaffold for BACE1 inhibitor.
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Report
(4 results)
Research Products
(17 results)
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[Journal Article] Chemical Dynamic Kinetic Resolution and S/R Interconversion of Unprotected α-Amino Acids2014
Author(s)
Takeda, R.; Kawamura, A.; Kawashima, A.; Sato, T.; Moriwaki, H.; Izawa, K.; Akaji, K.; Wang, S.; Liu, H.; Acena, J. L.; Soloshonok, V. A.
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Journal Title
Angew. Chem. Int. Ed.
Volume: 53
Issue: 45
Pages: 12214-12217
DOI
Related Report
Peer Reviewed
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[Journal Article] Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: Design, synthesis, biological evaluation, and docking studies2013
Author(s)
Thanigaimalai, P.; Konno, S.; Yamamoto, T.; Koiwai, Y.; Taguchi, A.; Takayama, K.; Yakushiji, F.; Akaji, K.; Chen, S.-E.;Naser-Tavakolian, A.; Schon, A.; Freire, E.; Hayashi, Y.
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Journal Title
Eur. J. Med. Chem.
Volume: 68
Pages: 372-384
DOI
Related Report
Peer Reviewed
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