1989 Fiscal Year Final Research Report Summary
Development of Antithrombotic Peptide Analogues with PDE Inhibitory Activity
| Project/Area Number |
62570985
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | Osaka University |
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Principal Investigator |
MIMURA Tsutomu Osaka Univ., Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (40028832)
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| Co-Investigator(Kenkyū-buntansha) |
OKABE Masaru Osaka Univ., Faculty of Pharmaceutical Sciences, Assistant Researcher, 薬学部, 助手 (30089875)
KOHAMA Yasuhiro Osaka Univ., Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (60028868)
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| Project Period (FY) |
1987 – 1989
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| Keywords | peptide / peptide analogue / structure-activity relationship / antithrombotic action / hydroxyproline / proline |
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| Research Abstract |
A hexapeptide (AAP) isolated from bovine atria and identified as Gly-Pro-Hyp-Gly-Ala-Gly, showed a protective effect against several experimental thrombotic models in vivo via its inhibitory action on Ca, calmodulin- dependent phosphodiesterase (PDE). In order to increase this unique activity of A4P and to develop a new potent anti-thrombotic agent. 15 kinds of its analogues were synthesized and their activities were evaluated in Ca- induced arrhythmia in mice.
Among synthesized fragments of AAP, only Pro-Hyp-Gly-Ala-Gly (P-5) showed the same activity as AAP. Several chemical modifications were performed on a P-5 molecule. A 3-(4-hydrouphem-1) propionylation of the imino nitrogen of Pro in P-5 (corresponding to N-3-[4-hydroxypherxyilpropionyl] Pro-Hyp-Gly-Ala-Gly, termed as HP-5) led to strongly increased activity (approximately 10 times). Furthermore, the prolyl residue was more favorable than the hydroxyprolyl residue for the activity of HP-5.
Conclusively, N-3-(4-hydroxyphenyl)propionyl Pro-Pro-Gly-Ala-Gly, termed as [Pro^2]HP-5. was the most suitable analogue for a candidate of antithrombotic agent, as shown from the present structure-activity relationship research.
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