title: Isolation and structure of antagonists of chemokine receptor (CCR5).
abstract: Human CCR5 is a G-coupled receptor that binds to the envelope protein gp120 and CD4 and mediates the HIV-1 viral entry into the cells. The blockade of this binding by a small molecule receptor antagonist could lead to a new mode of action agent for HIV-1 and AIDS. Screening of natural product extracts led to the identification of anibamine (1), a novel pyridine quaternary alkaloid as a TFA salt, from Aniba sp.; ophiobolin C from fermentation extracts of fungi Mollisia sp.; and 19,20-epoxycytochalasin Q from Xylaria sp. Formation of the TFA salt of anibamine is plausibly an artifact of the isolation. The identity of the natural counterion is unknown. Anibamine.TFA competed for the binding of 125I-gp120 to human CCR5 with an IC50 of 1 microM. Ophiobolin C and 19,20-epoxycytochalasin Q exhibited binding IC50) values of 40 and 60 microM, respectively.
authors.affiliation: Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
authors.forename: Hiranthi
authors.initials: H
authors.lastname: Jayasuriya
authors.forename: Kithsiri B
authors.initials: KB
authors.lastname: Herath
authors.forename: John G
authors.initials: JG
authors.lastname: Ondeyka
authors.forename: Jon D
authors.initials: JD
authors.lastname: Polishook
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Bills
authors.forename: Anne W
authors.initials: AW
authors.lastname: Dombrowski
authors.forename: Marty S
authors.initials: MS
authors.lastname: Springer
authors.forename: Sal
authors.initials: S
authors.lastname: Siciliano
authors.forename: Lorraine
authors.initials: L
authors.lastname: Malkowitz
authors.forename: Manuel
authors.initials: M
authors.lastname: Sanchez
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Guan
authors.forename: Suroojnauth
authors.initials: S
authors.lastname: Tiwari
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Stevenson
authors.forename: Robert P
authors.initials: RP
authors.lastname: Borris
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens / Q000378:metabolism*; D003572:Cytochalasins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D005658:Fungi / Q000737:chemistry*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D019770:Lauraceae / Q000737:chemistry*; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D054830:Sesterterpenes; D013729:Terpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: C488245:19,20-epoxycytochalasin Q; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D003572:Cytochalasins; D015699:HIV Envelope Protein gp120; D011725:Pyridines; D054830:Sesterterpenes; D013729:Terpenes; C488244:anibamine; C101214:ophiobolin C