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.
引用
收藏
页码:63 / 70
页数:8
相关论文
共 33 条
[31]   FORMATION OF A STABLE COMPLEX BETWEEN THE HUMAN-IMMUNODEFICIENCY-VIRUS INTEGRASE PROTEIN AND VIRAL-DNA [J].
VINK, C ;
LUTZKE, RAP ;
PLASTERK, RHA .
NUCLEIC ACIDS RESEARCH, 1994, 22 (20) :4103-4110
[32]   The role of manganese in promoting multimerization and assembly of human immunodeficiency virus type 1 integrase as a catalytically active complex on immobilized long terminal repeat substrates [J].
Wolfe, AL ;
Felock, PJ ;
Hastings, JC ;
Blau, CU ;
Hazuda, DJ .
JOURNAL OF VIROLOGY, 1996, 70 (03) :1424-1432
[33]   Hydrazide-containing inhibitors of HIV-1 integrase [J].
Zhao, H ;
Neamati, N ;
Sunder, S ;
Hong, HX ;
Wang, SM ;
Milne, GWA ;
Pommier, Y ;
Burke, TR .
JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (06) :937-941