Article

Palmitic Acid Analogs Exhibit Nanomolar Binding Affinity for the HIV-1 CD4 Receptor and Nanomolar Inhibition of gp120-to-CD4 Fusion

Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
PLoS ONE (Impact Factor: 3.53). 08/2010; 5(8):e12168. DOI: 10.1371/journal.pone.0012168
Source: PubMed

ABSTRACT We recently reported that palmitic acid (PA) is a novel and efficient CD4 fusion inhibitor to HIV-1 entry and infection. In the present report, based on in silico modeling of the novel CD4 pocket that binds PA, we describe discovery of highly potent PA analogs with increased CD4 receptor binding affinities (K(d)) and gp120-to-CD4 inhibition constants (K(i)). The PA analogs were selected to satisfy Lipinski's rule of drug-likeness, increased solubility, and to avoid potential cytotoxicity.
PA analog 2-bromopalmitate (2-BP) was most efficacious with K(d) approximately 74 nM and K(i) approximately 122 nM, ascorbyl palmitate (6-AP) exhibited slightly higher K(d) approximately 140 nM and K(i) approximately 354 nM, and sucrose palmitate (SP) was least efficacious binding to CD4 with K(d) approximately 364 nM and inhibiting gp120-to-CD4 binding with K(i) approximately 1486 nM. Importantly, PA and its analogs specifically bound to the CD4 receptor with the one to one stoichiometry.
Considering observed differences between K(i) and K(d) values indicates clear and rational direction for improving inhibition efficacy to HIV-1 entry and infection. Taken together this report introduces a novel class of natural small molecules fusion inhibitors with nanomolar efficacy of CD4 receptor binding and inhibition of HIV-1 entry.

Download full-text

Full-text

Available from: Alexander Shekhtman, Jun 17, 2014
0 Followers
 · 
134 Views
  • Source
    • "It was shown that lauric acid had antimicrobial activity against Propionibacterium acnes, Staphylococcus aureus, and S. epidermidis (Coimbra and Jorge 2012; Nakatsuji et al. 2009). Palmitic acid inhibits HIV-1 infection and is safe for tissues and probiotic bacteria (Paskaleva et al. 2010; Lin et al. 2011). This compound was identified in the essential oil of Viola tianshanica (Yang et al. 2011), Scutellaria orientalis ssp. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The essential oil of Trollius europaeus flowers obtained by hydrodistillation was analyzed by gas chromatography coupled with mass spectrometry (GC–MS). The compounds giving fragrance of essential oils commonly used in perfumery 3,7-dimethyl-1,6-octadien-3-ol, nonanal, 3-methyl-2-pent-2-enyl-cyclopent-2-enone and oxacycloheptadec-8-en-2-one, rare in the Plant Kingdom, were tentatively identified. In the analyzed essential oil, the saturated fatty acids hexadecanoic acid (7.54 %), tetradecanoic acid (4.24 %), dodecanoic acid (3.10 %) and unsaturated fatty acids 9,12,15-octadecatrienoic acid (3.47 %), hydrocarbons, namely eicosane (20.03 %), hexadecane (8.63 %) and 1,2-benzenedicarboxylic acid (2.39 %), were also found.
    Acta Physiologiae Plantarum 05/2012; 35(5). DOI:10.1007/s11738-012-1180-y · 1.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A number of 5'-O-fatty acyl derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (stavudine, d4T) were synthesized and evaluated for anti-HIV activities against cell-free and cell-associated virus, cellular cytotoxicity, and cellular uptake studies. The conjugates were found to be more potent than d4T. Among these conjugates, 5'-O-12-azidododecanoyl derivative of d4T (2), displaying EC(50) = 3.1-22.4 μM, showed 4- to 9-fold higher activities than d4T against cell-free and cell-associated virus. Cellular uptake studies were conducted on CCRF-CEM cell line using 5(6)-carboxyfluorescein derivatives of d4T attached through β-alanine (9) or 12-aminododecanoic acid (10) as linkers. The fluorescein-substituted analog of d4T with long chain length (10) showed 12- to 15-fold higher cellular uptake profile than the corresponding analog with short chain length (9). These studies reveal that conjugation of fatty acids to d4T enhances the cellular uptake and anti-HIV activity of stavudine.
    Bioorganic & medicinal chemistry letters 02/2011; 21(7):1917-21. DOI:10.1016/j.bmcl.2011.02.070 · 2.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Approximately 80% of all new HIV-1 infections are acquired through sexual contact. Currently, there is no clinically approved microbicide, indicating a clear and urgent therapeutic need. We recently reported that palmitic acid (PA) is a novel and specific inhibitor of HIV-1 fusion and entry. Mechanistically, PA inhibits HIV-1 infection by binding to a novel pocket on the CD4 receptor and blocks efficient gp120-to-CD4 attachment. Here, we wanted to assess the ability of PA to inhibit HIV-1 infection in cervical tissue ex vivo model of human vagina, and determine its effect on Lactobacillus (L) species of probiotic vaginal flora. Our results show that treatment with 100-200 µM PA inhibited HIV-1 infection in cervical tissue by up to 50%, and this treatment was not toxic to the tissue or to L. crispatus and jensenii species of vaginal flora. In vitro, in a cell free system that is independent of in vivo cell associated CD4 receptor; we determined inhibition constant (Ki) to be ∼2.53 µM. These results demonstrate utility of PA as a model molecule for further preclinical development of a safe and potent HIV-1 entry microbicide inhibitor.
    PLoS ONE 09/2011; 6(9):e24803. DOI:10.1371/journal.pone.0024803 · 3.53 Impact Factor
Show more