| Project/Area Number |
63480463
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
SEZAKI Hitoshi Kyoto University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (50025681)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAKURA Yoshinobu Kyoto University, Faculty of Pharmaceutical Sciences, Instructor, 薬学部, 助手 (30171432)
YAMAMOTO Akira Kyoto University, Faculty of Pharmaceutical Sciences, Instructor, 薬学部, 助手 (00166779)
HASHIDA Mitsuru Kyoto University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (20135594)
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| Project Period (FY) |
1988 – 1989
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| Project Status |
Completed (Fiscal Year 1989)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 1989: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1988: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | Peptide Drug / Chemical Modification / Electric Charge / Macromolecular Modification / Polyethyleneglycol / Dextran / Receptor-mediated Transport / Superoxide Dismutase / 大豆トリプシンインヒビター / ウリカーゼ / 体内挙動 |
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| Research Abstract |
Chemical modification of peptide drugs seems to be a promising way to control and improve their biopharmaceutical properties. In order to establish a systematic strategy for this approach, we have investigated relationships between chemical structures, physicochemical and biological properties, and systemic disposition characteristics. These studies include modifications via introduction of electric charge, carbohydrate moiety, and macromolecules which increase total molecular size or hinder specific biological recognition. Especially, studies were focused on the utilization of carbohydrate derivatives.
Glomerular filtration in the kidney, hepatic uptake, and degradation by a protease are major processes which determine in vivo disposition features of proteinous drugs. We have succeeded to overcome these problems and prolong biological half-lives of peptides by utilizing the conjugation with dextran and polyanionic carboxymethyl-dextran. By applying these-methods, remarkable prolongation of biological half-life and therapeutic activity was obtained for uricase, superoxide dismutase, and soybean trypsin inhibitor. On the other hand, introduction of galactose or mannose enhanced organ uptake via receptor-mediated endocytosis. Those observations would offer important basic information for establishing a methodology of controlling in vivo fate of peptide drugs.
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