Palmitic Acid Is a Novel CD4 Fusion Inhibitor That Blocks HIV Entry and Infection

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.

Lee, David Y.-W.
Lin, Xudong
Paskaleva, Elena E.
Liu, Yanze
Puttamadappa, Shadakshara S.
Thornber, Carol
Drake, James R.
Habulin, Maja
Shekhtman, Alexander
Canki, Mario
Item Type: 
Journal Article
Publication Title: 
AIDS research and human retroviruses
Journal Abbreviation: 
AIDS Res. Hum. Retroviruses
Publication Date: 
Dec 2009
Publication Year: 
Library Catalog: 
NCBI Published Medical (?)
PMID: 20001317 PMCID: PMC2828184

Turabian/Chicago Citation

David Y.-W. Lee, Xudong Lin, Elena E. Paskaleva, Yanze Liu, Shadakshara S. Puttamadappa, Carol Thornber, James R. Drake, Maja Habulin, Alexander Shekhtman and Mario Canki. Dec 2009. "Palmitic Acid Is a Novel CD4 Fusion Inhibitor That Blocks HIV Entry and Infection." AIDS research and human retroviruses 25: 12: 1231-1241. 10.1089/aid.2009.0019.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1089/aid.2009.0019 | issn = 1931-8405 | volume = 25 | pages = 1231-1241 | last = Lee | first = David Y.-W. | coauthors = Lin, Xudong, Paskaleva, Elena E., Liu, Yanze, Puttamadappa, Shadakshara S., Thornber, Carol, Drake, James R., Habulin, Maja, Shekhtman, Alexander, Canki, Mario | title = Palmitic Acid Is a Novel CD4 Fusion Inhibitor That Blocks HIV Entry and Infection | journal = AIDS research and human retroviruses | date = Dec 2009 | pmid = | pmc = }} </ref>