Summary of Research Project Results under JSPS FY2001
"Research for the Future Program"

1.Research Institution Kumamoto University
2.Research Area Life Sciences
3.Research Field Infectious Diseases and Bioregulation
4.Term of Project FY 1997 〜 FY 2001
5.Project Number 97L00705
6.Title of Project Study of Pathophysiology of HIV-1 Infection and Development of AIDS Therapy

7.Project Leader
Name Institution,Department Title of Position
Hiroaki, MITSUYA Kumamoto University , School of Medicine Professor

8.Core Members

Names Institution,Department Title of Position
Shuzo, MASTUSHITA Kumamoto University, Center for AIDS Research Professor
Hiroyuki, MORIUCHI Nagasaki University, School of Medicine Professor
Masanori, BABA Kagoshima University, School of Medicine Professor

9.Summary of Research Results

 In this project, we attempted to study the pathophysiology of HIV-1 infection and to identify/develop novel anti-HIV-1 agents which may serve as therapeutic agents for AIDS. We previously identified a unique set of amino acid substitutions in the polymerase region of reverse transcriptase (RT) which confer on HIV-1 a high multitude of resistance against multiple nucleoside RT inhibitors (NRTIs) in patients receiving a long-term antiviral chemotherapy including multiple NRTIs. We further clarified the virological and enzymologic profiles and mechanism of the emergence of such resistant variants (HIV-1MDR). Moreover, we demonstrated that certain non-cleavage site amino acid substitutions in Gag protein of the virus recover the reduced replicative fitness of HIV-1 caused by mutations in protease (Gatanaga et al. J Biol Chem 277: 5952, 2002). We also designed, synthesized, and identified several novel NRTIs potent against wild-type HIV-1 and various HIV-1MDRs. Such agents include (i) 2'-β-fluoro-2',3'-dideoxyadenosine, (ii) methylenecyclopropane NRTIs, and (iii) 4'-ethynyl-2',3'-dideoxynucleosides. We further designed and identified two novel protease inhibitors (PIs), JE2147/AG1776 (Yoshimura et al. PNAS 96: 8675, 1999) and UIC94003/TMC126 (Yoshimura et al. J Virol 76:1349, 2002). The former contains a flexible P2’ moiety which is important for its potency toward wild type and mutant viruses, suggesting that the use of flexible components may open a new avenue for designing PIs which resist the emergence of PI-resistant HIV-1. The latter contains a unique component which has a close contact with the main chains of the protease active site amino acids, suggesting that the introduction of such a component interacting with main chains of key amino acids and seeking a unique inhibitor-enzyme contact profile should provide a framework for developing novel PIs. Through our efforts to determine the role of NH2 terminus of LD78β, a variant of human MIP-1α, we found that such a chemokine, if properly modified, may serve as effective anti-HIV-1 therapeutics while preserving chemokine-chemokine receptor interactions (Miyakawa et al. J Biol Chem 277: 4649, 2002). Furthermore, we identified a series of novel low molecular weight spirodiketopiperazine (SDP) derivatives which potently inhibit R5-HIV-1 infection and replication through their antagonistic effects on CCR5. (Maeda et al. J Biol Chem 276: 35194, 2002). One such compound E913 and its analogs are acid-resistant and orally bioavailabile in rodents. Several of such SDP derivatives have been considered for preclinical and early clinical developments.

10.Key Words

(1)AIDS、(2)HIV、(3)reverse trascriptase inhibitor
(4)protease inhibitor、(5)entry inhibitor、(6)drug resistance