Palmitic acid is a novel cd4 fusion inhibitor that blocks HIV entry and infection
Date of Original Version
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 100μM PA inhibited both X4 and R5 independent infection in the T cell line up to 70%. Treatment with 22μM PA inhibited X4 infection in primary peripheral blood lymphocytes (PBL) up to 95% and 100μM 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 10-6M 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 Kd ∼1.5±0.2μM, 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. © 2009, Mary Ann Liebert, Inc.
Publication Title, e.g., Journal
AIDS Research and Human Retroviruses
Lee, David Y., Xudong Lin, Elena E. Paskaleva, Yanze Liu, Shadakshara S. Puttamadappa, Carol Thornber, James R. Drake, Maja Habulin, Alexander Shekhtman, and Mario Canki. "Palmitic acid is a novel cd4 fusion inhibitor that blocks HIV entry and infection." AIDS Research and Human Retroviruses 25, 12 (2009). doi: 10.1089/aid.2009.0019.