title: Lamellarin alpha 20-sulfate, an inhibitor of HIV-1 integrase active against HIV-1 virus in cell culture.
abstract: HIV-1 integrase is an attractive target for anti-retroviral chemotherapy, but to date no clinically useful inhibitors have been developed. We have screened diverse marine natural products for compounds active against integrase in vitro and found a series of ascidian alkaloids, the lamellarins, that show selective inhibition. A new member of the family named lamellarin alpha 20-sulfate (1), the structure of which was determined from spectroscopic data, displayed the most favorable therapeutic index. The site of action of lamellarin alpha 20-sulfate on the integrase protein was mapped by testing activity against deletion mutants of integrase. Inhibition of isolated catalytic domain was detectable though weaker than inhibition of full length integrase; possibly lamellarin alpha 20-sulfate binds a site composed of multiple integrase domains. Lamellarin alpha 20-sulfate also inhibited integration in vitro by authentic HIV-1 replication intermediates isolated from infected cells. Lamellarin alpha 20-sulfate was tested against wild type HIV using the MAGI indicator cell assay and found to inhibit early steps of HIV replication. To clarify the inhibitor target, we tested inhibition against an HIV-based retroviral vector bearing a different viral envelope. Inhibition was observed, indicating that the HIV envelope cannot be the sole target of lamellarin alpha 20-sulfate in cell culture. In addition, these single round tests rule out action against viral assembly or budding. These findings provide a new class of compounds for potential development of clinically useful integrase inhibitors.
authors.affiliation: Organic Chemistry Division-I, Natural Products Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: M V
authors.initials: MV
authors.lastname: Reddy
authors.forename: M R
authors.initials: MR
authors.lastname: Rao
authors.forename: D
authors.initials: D
authors.lastname: Rhodes
authors.forename: M S
authors.initials: MS
authors.lastname: Hansen
authors.forename: K
authors.initials: K
authors.lastname: Rubins
authors.forename: F D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Y
authors.initials: Y
authors.lastname: Venkateswarlu
authors.forename: D J
authors.initials: DJ
authors.lastname: Faulkner
mesh_terms: D000818:Animals; D002460:Cell Line; D003374:Coumarins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology / Q000633:toxicity; D015247:Deoxyribonuclease HindIII / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines; D008977:Molluscum contagiosum virus / Q000201:enzymology; D011758:Pyrroles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology / Q000633:toxicity; D059004:Topoisomerase I Inhibitors; D014561:Urochordata / Q000737:chemistry*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D003374:Coumarins; D004791:Enzyme Inhibitors; D019428:HIV Integrase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; D011758:Pyrroles; D059004:Topoisomerase I Inhibitors; C119474:lamellarin alpha 20-sulfate; D019427:HIV Integrase; D015247:Deoxyribonuclease HindIII