| 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 |
| 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