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Isolation and characterization of novel human immunodeficiency virus integrase inhibitors from fungal metabolites
被引:85
作者:
Hazuda, D
[1
]
Blau, CU
Felock, P
Hastings, J
Pramanik, B
Wolfe, A
Bushman, F
Farnet, C
Goetz, M
Williams, M
Silverman, K
Lingham, R
Singh, S
机构:
[1] Merck Res Labs, Dept Antiviral Res, West Point, PA 19486 USA
[2] Salk Inst Biol Studies, Infect Dis Lab, La Jolla, CA 92037 USA
[3] Merck Res Labs, Dept Nat Prod Drug Discovery, Rahway, NJ 07065 USA
关键词:
HIV;
integrase;
equisetin;
fungal metabolites;
D O I:
10.1177/095632029901000202
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
We have identified a series of novel inhibitors of human immunodeficiency virus type 1 (HIV-1) integrase by randomly screening natural product extracts using an in vitro biochemical assay designed to identify inhibitors of integrase-catalysed strand transfer. Equisetin recovered from the fungus Fusarium heterosporum and a novel enantiomeric homologue of equisetin from Phoma sp. were isolated as inhibitors of HIV-1 integrase in vitro. Two additional analogues, a novel decalin derivative, integric acid, and oteromycin were also discovered to be inhibitors of integrase. Equisetin and related compounds inhibit 3' end-processing and strand transfer as well as disintegration catalysed by either the full-length enzyme or the truncated integrase core domain (amino acids 50-212). These compounds also inhibit strand transfer reactions catalysed by stable complexes assembled in vitro and integration reactions catalysed by pre-integration complexes isolated from HIV-l-infected cells. The compounds described in this report are structurally novel and mechanistically distinct from many previously described inhibitors of HIV-1 integrase. These results demonstrate the utility of using an appropriately configured assay to identify compounds that are effective post-assembly and the potential of isolating novel integrase inhibitors from complex natural product extracts.
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页码:63 / 70
页数:8
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