Isolation and characterization of novel human immunodeficiency virus integrase inhibitors from fungal metabolites

We have identified a series of novel inhibitors of human immunodeficiency v irus type 1 (HIV-1) integrase by randomly screening natural product extract s using an in vitro biochemical assay designed to identify inhibitors of in tegrase-catalysed strand transfer. Equisetin recovered from the fungus Fusa rium heterosporum and a novel enantiomeric homologue of equisetin from Phom a sp. were isolated as inhibitors of HIV-1 integrase in vitro. Two addition al analogues, a novel decalin derivative, integric acid, and oteromycin wer e also discovered to be inhibitors of integrase. Equisetin and related comp ounds inhibit 3' end-processing and strand transfer as well as disintegrati on catalysed by either the full-length enzyme or the truncated integrase co re domain (amino acids 50-212). These compounds also inhibit strand transfe r reactions catalysed by stable complexes assembled in vitro and integratio n reactions catalysed by pre-integration complexes isolated from HIV-l-infe cted cells. The compounds described in this report are structurally novel a nd mechanistically distinct from many previously described inhibitors of HI V-1 integrase. These results demonstrate the utility of using an appropriat ely configured assay to identify compounds that are effective post-assembly and the potential of isolating novel integrase inhibitors from complex nat ural product extracts.