1995 Fiscal Year Final Research Report Summary
Joint study on protease-targeted anti-AIDS drugs
| Project/Area Number |
05044191
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Institution | Kyoto Pharmaceutical University |
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Principal Investigator |
KISO Yoshiaki Kyoto Pharmaceutical University, 薬学部, 教授 (40089107)
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| Co-Investigator(Kenkyū-buntansha) |
YARCHOAN Robert National Cancer Institute, Retroviral Dis, Chief
MITSUYA Hiroaki National Cancer Institute, Experimental R, Chief
AKAJI Kenichi Kyoto Pharmaceutical University, 薬学部, 助教授 (60142296)
TAKADA Kanji Kyoto Pharmaceutical University, 薬学部, 教授
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| Project Period (FY) |
1993 – 1995
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| Keywords | HIV protease inhibitor / anti-AIDS drug / peptide mimic / activiral drug / anti-HIV drug / drug design / kynostatin / prodrug / peptide synthesis |
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| Research Abstract |
The HIV codes for a virus-specific aspartic protease responsible for processing the gag and gag-pol polyproteons and for the proliferation of the retrovirus. The HIV protease is considered as a potential target for the development of anti-AIDS agents.
Based on the substrate transition-state mimic concept and Phe-Pro as the virus specific cleavage sequence, we designed and synthesized a novel class of HIV protease inhibitors containing an unnatural amino acid, allophenylnorstatine (Apns) as a hydroxymethylcarbonyl isostere.After lead optimization study, the most excellent tripeptide inhibitor, kynostatin (KNI)-272 was adopted as the candidate for pharmacokinetic and clinical study. This year, we have carried out the following studies for the development of KNI-272 as an anti-HIV drug.
1.Preparation of a prodrug and large-scale synthesis of KNI-272. A water-soluble prodrug which is transformed to an active-form in vivo by intramolecular N-O acyl rearrangement was prepared. A highly efficie
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nt and stereoselective large-scale synthesis of KNI-272 was established for the pharmacokinetic study.
2.Synthesis of small-sized analogs of KNI-272. The smaller dipeptide analogs were synthesized and shown to have anti-HIV activity and good pharmacokinetic properties.
3.Determination of anti-HIV activity of KNI compounds was carried out using ATH8 cell line, peripheral blood cells from AIDS patients, and AZT-insensitive cells.
4.Pharmacokinetic analysis of KNI-272 in rats. Bioavailabilities were determined by oral and i.v. administration.
5.Examination of animal scale-up. Pharmacokinetic profiles were simulated using parameters obtained from rats, rabbits and beagle dogs.
6.Estimation of anti-HIV activity using HuPBMC-SCID mice as an HIV model. HIV was infected into severe combined immunodeficiency mice inoculated with human peripheral blood mononuclear cells and used for the study.
7.Clinical study of KNI-272 in AIDS patients.
8.Examination of interaction between KNI-272 and KNI-272-insensitive variant of HIV protease. Less
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