Inhibition of HIV-1 Infection in Ex Vivo Cervical Tissue Model of Human Vagina by Palmitic Acid; Implications for a Microbicide Development

University of Cape Town, South Africa
PLoS ONE (Impact Factor: 3.23). 09/2011; 6(9):e24803. DOI: 10.1371/journal.pone.0024803
Source: PubMed


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.

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Available from: Alexander Shekhtman, Jul 24, 2014
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    • "Considering that the CD4 glycoprotein is the obligatory HIV receptor regardless of HIV coreceptor usage, the PA and 2-BP represent small chemical entity (SCE) molecule binding to the specified CD4 cavity that explains the observed entry inhibition of both X4- and R5-tropic HIV [3], [4]. We also showed inhibition of R5 HIV-1 productive infection in human cervix tissue ex vivo model experiments, demonstrating opportunity for topical microbicide development aimed at preventing sexual HIV transmission [5], which remains the main cause of HIV transmission. "
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    ABSTRACT: AIDS is a global pandemic that has seen the development of novel and effective treatments to improve the quality of life of those infected and reduction of spread of the disease. Palmitic Acid (PA), which we identified and isolated from Sargassum fusiforme, is a naturally occurring fatty acid that specifically inhibits HIV entry by binding to a novel pocket on the CD4 receptor. We also identified a structural analogue, 2-bromopalmitate (2-BP), as a more effective HIV entry inhibitor with a 20-fold increase in efficacy. We have used the structure-activity relationship (SAR) of 2-BP as a platform to identify new small chemical molecules that fit into the various identified active sites in an effort to identify more potent CD4 entry inhibitors. To validate further drug development, we tested the PA and 2-BP scaffold molecules for genotoxic potential. The FDA and International Conference on Harmonisation (ICH) recommends using a standardized 3-test battery for testing compound genotoxicity consisting of the bacterial reverse mutation assay, mouse lymphoma assay, and rat micronucleus assay. PA and 2-BP and their metabolites tested negative in all three genotoxicty tests. 2-BP is the first derivative of PA to undergo pre-clinical screening, which will enable us to now test multiple simultaneous small chemical structures based on activity in scaffold modeling across the dimension of pre-clinical testing to enable transition to human testing.
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    • "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. "
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