title: Palmitic Acid Is a Novel CD4 Fusion Inhibitor  That Blocks HIV Entry and Infection.
abstract: The high rate of HIV-1 mutation and the frequent sexual transmission highlight the need for novel therapeutic modalities with broad activity against both CXCR4 (X4) and CCR5 (R5)-tropic viruses. We investigated a large number of natural products, and from Sargassum fusiforme we isolated and identified palmitic acid (PA) as a natural small bioactive molecule with activity against HIV-1 infection. Treatment with 100 microM PA inhibited both X4 and R5 independent infection in the T cell line up to 70%. Treatment with 22 microM PA inhibited X4 infection in primary peripheral blood lymphocytes (PBL) up to 95% and 100 microM PA inhibited R5 infection in primary macrophages by over 90%. Inhibition of infection was concentration dependent, and cell viability for all treatments tested remained above 80%, similar to treatment with 10(-6)M nucleoside analogue 2', 3'-dideoxycytidine (ddC). Micromolar PA concentrations also inhibited cell-to-cell fusion and specific virus-to-cell fusion up to 62%. PA treatment did not result in internalization of the cell surface CD4 receptor or lipid raft disruption, and it did not inhibit intracellular virus replication. PA directly inhibited gp120-CD4 complex formation in a dose-dependent manner. We used fluorescence spectroscopy to determine that PA binds to the CD4 receptor with K(d) approximately 1.5 +/- 0.2 microM, and we used one-dimensional saturation transfer difference NMR (STD-NMR) to determined that the PA binding epitope for CD4 consists of the hydrophobic methyl and methelene groups located away from the PA carboxyl terminal, which blocks efficient gp120-CD4 attachment. These findings introduce a novel class of antiviral compound that binds directly to the CD4 receptor, blocking HIV-1 entry and infection. Understanding the structure-affinity relationship (SAR) between PA and CD4 should lead to the development of PA analogs with greater potency against HIV-1 entry.
authors.affiliation: Mailman Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA.
authors.forename: David Y-W
authors.initials: DY
authors.lastname: Lee
authors.forename: Xudong
authors.initials: X
authors.lastname: Lin
authors.forename: Elena E
authors.initials: EE
authors.lastname: Paskaleva
authors.forename: Yanze
authors.initials: Y
authors.lastname: Liu
authors.forename: Shadakshara S
authors.initials: SS
authors.lastname: Puttamadappa
authors.forename: Carol
authors.initials: C
authors.lastname: Thornber
authors.forename: James R
authors.initials: JR
authors.lastname: Drake
authors.forename: Maja
authors.initials: M
authors.lastname: Habulin
authors.forename: Alexander
authors.initials: A
authors.lastname: Shekhtman
authors.forename: Mario
authors.initials: M
authors.lastname: Canki
mesh_terms: D015704:CD4 Antigens / Q000187:drug effects / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D002459:Cell Fusion; D002460:Cell Line; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D019308:Palmitic Acid / Q000737:chemistry / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000187:drug effects / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000378:metabolism; D044647:Sargassum / Q000737:chemistry; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
chemical_list: D015704:CD4 Antigens; D004791:Enzyme Inhibitors; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019308:Palmitic Acid