1989 Fiscal Year Final Research Report Summary
Search for antiviral agents based on the inhibition of viral specific enzymes
| Project/Area Number |
63571044
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
INOUYE Yoshio Hiroshima University School of Medicine, Associate Professor, 医学部, 助教授 (00136053)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Shoshiro Hiroshima University School of Medicine, Professor, 医学部, 教授 (40013304)
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| Project Period (FY) |
1988 – 1989
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| Keywords | Reverse transcriptase / Retroviruses / Acquired immunodeficiency virus / Avian myeloblastosis virus / Streptonigrin / Quinone compounds / Polyoxometalates |
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| Research Abstract |
The inhibition of human immunodeficiency virus (HIV) reverse transcriptase by certain antibiotics and related compounds was studied in comparison with that of avian myeloblastosis virus (AMV) reverse transcriptase and cellular DNA polymerases. Antitumor antibiotic streptonigrin and synthetic quinone compounds were active against both HIV and AMV enzymes. MV enzyme was more sensitive than HIV enzyme to some antibiotics such as colistin and enduracidins A and B, whereas the streptonigrin alkyl esters inhibited HIV reverse transcriptase only. As for quinone compounds, we proposed the existence of a specific site of interaction, reffered to as a "quinone pocket", on AMV reverse transcriptase. This putative structure will be conserved on a wide range of reverse transcriptases, among which HIV enzyme is included. More than 100 quinone compounds, specially para- and iso-quinoline quinones, were synthesized to study the structure-activity correlationship. In general, ortho-quinoline quinones were found to be more active against AMV reverse transcriptase and less toxic toward mouse lymphoblastoma L5178Y cells, suggesting the superiority of the former to the latter as a specific inhibitor of replication of retroviruses.
Among heteropolyoxometalates, Keggin-type heteropolyoxotungstates represented by PM-19 K_7[PTi_2W_<10>O_<40>]-6H_2O proved to be potent inhibitors of HIV replication in vitro. HPA 23 has been known to be an inhibitor of reverse transcriptase. HPA 23 was applied to clinical cases for the first time in this group of compounds. However, the effect of HPA 23 on the the replication of HIV in vitro was negligible as compared to that of PM-19. The blocked viral adsorption to host cells is critical to the inhibition of HIV replication by PM-19.
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