title: Isolation, structure, and HIV-1-integrase inhibitory activity of structurally diverse fungal metabolites.
abstract: HIV-1 integrase is a critical enzyme for replication of HIV, and its inhibition is one of the most promising new drug strategies for anti-retroviral therapy, with potentially significant advantages over existing therapies. In this report, a series of HIV-1 inhibitors isolated from the organic extract of fermentations from terrestrial fungi is described. These fungal species, belonging to a variety of genera, were collected from throughout the world following the strict guidelines of Rio Convention on Biodiversity. The polyketide- and terpenoid-derived inhibitors are represented by two naphthoquinones, a biphenyl and two triphenyls, a benzophenone, four aromatics with or without catechol units, a linear aliphatic terpenoid, a diterpenoid, and a sesterterpenoid. These compounds inhibited the coupled and strand-transfer reaction of HIV-1 integrase with an IC(50) value of 0.5-120 micro M. The bioassay-directed isolation, structure elucidation, and HIV-1 inhibitory activity of these compounds are described.
authors.affiliation: Natural Products Chemistry, Merck Research Laboratories, P. O. Box 2000, Rahway, New Jersey 07065, USA. sheo_singh@merck.com
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.forename: Hiranthi
authors.initials: H
authors.lastname: Jayasuriya
authors.forename: Raymond
authors.initials: R
authors.lastname: Dewey
authors.forename: Jon D
authors.initials: JD
authors.lastname: Polishook
authors.forename: Anne W
authors.initials: AW
authors.lastname: Dombrowski
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Zink
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Guan
authors.forename: Javier
authors.initials: J
authors.lastname: Collado
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Platas
authors.forename: Fernando
authors.initials: F
authors.lastname: Pelaez
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Felock
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
mesh_terms: D000475:Alkenes / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D000880:Anthraquinones / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D001230:Aspergillus / Q000378:metabolism; D001713:Biphenyl Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D002109:Caffeic Acids / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D004952:Esters / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D005285:Fermentation; D005656:Fungal Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D019427:HIV Integrase / Q000378:metabolism*; D007218:Industrial Microbiology; D009005:Monosaccharides / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D010407:Penicillium / Q000378:metabolism; D011753:Pyrones / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D054830:Sesterterpenes; D032901:Talaromyces / Q000378:metabolism; D013729:Terpenes / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D013730:Terphenyl Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism
chemical_list: D000475:Alkenes; D000880:Anthraquinones; D001713:Biphenyl Compounds; D002109:Caffeic Acids; D004791:Enzyme Inhibitors; D004952:Esters; D005227:Fatty Acids; D005656:Fungal Proteins; D009005:Monosaccharides; D011753:Pyrones; D054830:Sesterterpenes; D013729:Terpenes; D013730:Terphenyl Compounds; C117996:coprophilin; C002884:ophiobolins; C401213:roselipin 2A; C029548:rugulosin; C095643:altenusin; C010790:terphenyllin; D019427:HIV Integrase; C007946:hispidin; C040048:caffeic acid