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Design and Synthesis of New Generation anti-HIV agents Based on the X-ray analysis of Inhibitor-RT Complexes

Research Project

Project/Area Number 09672159
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionShowa University

Principal Investigator

TANAKA Hiromichi  Showa University, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (50109477)

Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
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)
KeywordsAIDS / Reverse Transcriptase / HIV-1 / Allosteric Inhibitor / Resistant Virus / Amino Acid Mutation / NNRTI
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).

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (5 results)

All Other

All Publications (5 results)

  • [Publications] H.Tanaka et al.: "Allosteric Inhibitors against HIV-1 RT : design and synthesis of MKC-442 analogues having ω-functionalized acyclic structure" Antiviral Chemistry and Chemotherapy. 9. 325-332 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Tanaka et al.: "Advances in Antiviral Drug Design Vol.3" Edited by E.De Clercq, JAI Press, Greenwich (印刷中), (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Tanaka et al.: "Allosteric Inhibitors against HIV-1 RT : design and synthesis of MKC-442 analogues having an omega-functionalized acyclic structure" Antiviral chemistry and chemotherapy. Vol.9. 325-332 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Tanaka et al.: "HEPT : From an Investigation of Lithiation of Nucleosides Towards a Rational Design of Non-Nucleoside Reverse Transcriptase Inhibitors of HIV-1" Advances in Antiviral Drug Design. Vol.3 (in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Tanaka et al.: "Allosteric Inhibitors against HIV-1 RT:design and synthesis of MKC-442 analegues having an ω-functionalized acyclic structure" Antiviral Chemistry and Chemotherapy. 9巻4号. 325-332 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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