Design and Synthesis of New Generation anti-HIV agents Based on the X-ray analysis of Inhibitor-RT Complexes
| Project/Area Number |
09672159
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Showa University |
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Principal Investigator |
TANAKA Hiromichi Showa University, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (50109477)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | AIDS / Reverse Transcriptase / HIV-1 / Allosteric Inhibitor / Resistant Virus / Amino Acid Mutation / NNRTI |
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| Research Abstract |
Anti-HIV- I agent MKC-442 (generic name : emivirine), 6-benzyl- 1-ethoxymethyl-5-isopropyluracil, is now under Phase IIb clinical study in USA.Two single amino acid mutations, either Tyrl8lCys or LyslO3Asn, have been found in the Reverse Transcriptase (RT) of MKC-442-resistant HIV-1. The purpose of this study was to design and to synthesize MKC-442 analogues which show the activity even to theresistant strains.
in the first finacial year, a series of compounds were design by computer-graphics based on the X-ray analysis data of the RT complexed with MKC-442. However, these compounds, having an omega-carbamoylalkyl substituent at the N1-position, showed uniformly lower activity than that of MKC-442, and were found not to be active against Tyrl8lCys.
in the second year, it was found that TNK-6123, 6-cyclohexylthio-l-ethoxymethyi-5-isopropyluracil, shows significant activity against the Tyrl8lCys mutant. A 3000-fold reduced sensitivity of MKC-442 to this mutant was improved to be only 90-fold less sensitive in the case of TNK-6 123. The RT complexed with TNK-6 123 was analyzed again by X-ray crystallography, and the result is to be published shortly (submitted).
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Report
(3 results)
Research Products
(5 results)
