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Molecular design and synthesis of HIV protease inhibitors with structurally constrained active conformation

Research Project

Project/Area Number 08457588
Research Category

Grant-in-Aid for Scientific Research (B)

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

Principal Investigator

KISO Yoshiki  Faculth of Pharmaceutical Sciences, Professor, 薬学部, 教授 (40089107)

Co-Investigator(Kenkyū-buntansha) KIMURA Tooru  Faculty of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (70204980)
Project Period (FY) 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 1996: ¥6,500,000 (Direct Cost: ¥6,500,000)
KeywordsHIV Protease Inhibitors / Enzyme・Inhibitor Complex / Substrate Transition State Analog / Peptide Synthesis / Conformational Analysis / X-ray Crystallography / Drug Resistant Virus / Anti-AIDS Drug / コンフォンメーション解析
Research Abstract

Based on the substrate-transition state concept of HIV protease inhibitors, we have succeeded to design, investigate the minimum site for enzyme-interaction and synthesize a highly selective and potent HIV protease inhibitor (KNI-272). These successful results are attributable to the analysis of enzyme-substrate (or-inhibitor) complexes focusing on enzyme reaction mechanism, and the molecular design of conformationally constrained mimics of substrate transition state in the enzyme active site. We further developed these methods to molecular design and synthesis of inhibitors with structurally constrained active conformation.
1. Synthesis of mutant HIV protease.
It has been already reported that in mutated HIV proteases 84-Ile is replaced with Val which interacts with Pl and Pl' subsites. Therefore we synthesized 84-Val HIV protease derivatives and examined the enzyme activity.
2. Synthesis of active site derivatives of HIV proteases.
HIV protease derivatives with isosteric amino acids at 25-Asp which participates in the interaction with the substrates. Since the HIV protease works as a dimer, we examined two types of combinations : native/isosteric and isosteric/isosteric.
3. Synthesis of HIV protease inhibitors.
Based on the substrate transition state concept, the amide bond of the cleavage sites, Phe-Pro and Tyr-Pro (Pl-Pl') characteristic to retroviral enzyme substrate was converted to the isosteric reduced-type, hydroxyethylene-type, dihydroxyethylene-type and others. Dipeptide derivatives with rigid structure were also synthesized.
4. Conformational analysis of the enzyme-substrate complex was carried out by using NMR and molecular modeling.
5. Fomation and analysis of enzyme-inhibitor complexes.
X-ray crystallography and NMR analysis of the enzyme-inhibitor complex revealed that water molecules play an important role in the interaction of enzyme and inhibitors and that the highly potent inhibitor has highly constrained conformation.

Report

(2 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Yoshiaki Kiso: "Design and synthesis of substrate-based peptidomimetic HIV protease inhibitors containing the hydroxymethylcarbonyl isostere." Biopolymers. 40・2. 235-244 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yun-Xing Wang: "Solution NMR Evidence That the HIV-1 Protease Catalytic Aspartyl Groups Have Different Ionization States in the Complex Formed with the Asymmetric Drug KNI-272." Biochemistry. 35・31. 9945-9950 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yasushi Ohno: "Solution conformations of KNI-272,a tripeptide HIV protease inhibitor designed on the basis of substrate transition state : Determined by NMR spectroscopy and simulated annealing calculations." Bioorg.Med.Chem.4・9. 1565-1572 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yun-Xing Wang: "Bound water molecules at the interface between the HIV-1 protease and a potent inhibitor,KNI-272,determined by MNR." J.Am.Chem.Soc.118・49. 12287-12290 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] A.Kiriyama: "Binding characteristics of KNI-272 to plasma proteins,a new potent tripeptide HIV protease inhibitor." Biopharmaceut.Drug Disp.17・9. 739-751 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Satoshi Yamaguchi: "Synthesis of HIV protease dipeptide inhibitors and prodrugs." Peptide Chemistry. 1996. 297-300 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yoshiaki Kiso: "Design and synthesis of substrate-based peptidomimetic HIV protease inhibitors containing the hydroxymethylcarbonyl isostere." Biopolymers. 40-2. 235-244 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yun-Xing Wang: "Solution NMR Evidence That the HIV-1 Protease Catalytic Aspartyl Groups Have Different Ionization States in the Complex Formed with the Asymmetric Drug KNI-272." Biochemistry. 35-31. 9945-9950 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yasushi Ohno: "Solution conformations of KNI-272, a trioeotide HIV protease inhibitor designed on the basis of substrate transition state : Determined by NMR spectroscopy and simulated annealing calculations." Bioorg.Med.Chem.4-9. 1565-1572 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yun-Xing Wang: "Bound water molecules at the interface between the HIV-1 protease and a potent inhibitor, KNI-272, determined by NMR." J.Am.Chem.Soc.118-49. 12287-12290 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] A.Kiriyama: "Binding characteristics of KNI-272 to plasma proteins, a new potent tripeptide HIV protease inhibitor." Bioharmaceut.Drug Disp.17-9. 735-751 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Satoshi Yamaguchi: "Synthesis of HIV protease dipeptide inhibitors and prodrugs." Peptide Chemistry. 1996. 297-300 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yoshiaki Kiso: "Disign and synthesis of substrate-based peptidomimetic HIV protease inhibitors containing the hydroxymethylcarbonyl isostere." Biopolymers. 40・2. 235-244 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 木曽良明: "AIDS治療薬としてのHIVプロテアーゼ阻害薬-変異ウイルスと人類の共生は可能か-." 医学のあゆみ. 177・13. 962-968 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yun-Xing Wang: "Solution NMR Evidence That the HIV-1 Protease Catalytic Aspartyl Groups Have Different Ionization States in the Complex Formed with the Asymmetric Drug KNI-272." Biochemistry. 35・31. 9945-9950 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yasushi Ohno: "Solution conformations of KNI-272,a tripeptide HIV protease inhibitor designed on the basis of substrate transition state : Determined by NMR spectroscopy and simulated annealing calculations." Bioorg.Med.Chem.4・9. 1565-1572 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yun-Xing Wang: "Bound water molecules at the interface between the HIV-1 protease and a potent inhibitor,KNI-272,determined by NMR." J.Am.Chem.Soc.118・49. 12287-12290 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] A.Kiriyama: "Binding characteristics of KNI-272 to plasma proteins,a new potent tripeptide HIV protease inhibitor." Biopharmaceut.Drug Disp.17・9. 739-751 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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