"Our results suggest that HIV-1 inhibitory molecules in PS extracts target HIV-1 envelope proteins, since virus particles bearing the heterologous VSV-G protein instead of HIV-1 proteins in their envelopes are much less sensitive to inhibition by PS extract. The mode-of-action of PS extract exhibits a combination of features that set it apart from approved anti-HIV-1 drugs and from investigational entry inhibitors including lectins , , polyanionic compounds ,  and synthetic anti-lipopolysaccharide peptides (SALPs) , of which several are under development as microbicides and drug candidates. For one, PS extract prevents attachment of virus particles to host cells. "
[Show abstract][Hide abstract] ABSTRACT: Global HIV-1 treatment would benefit greatly from safe herbal medicines with scientifically validated novel anti-HIV-1 activities. The root extract from the medicinal plant Pelargonium sidoides (PS) is licensed in Germany as the herbal medicine EPs®7630, with numerous clinical trials supporting its safety in humans. Here we provide evidence from multiple cell culture experiments that PS extract displays potent anti-HIV-1 activity. We show that PS extract protects peripheral blood mononuclear cells and macrophages from infection with various X4 and R5 tropic HIV-1 strains, including clinical isolates. Functional studies revealed that the extract from PS has a novel mode-of-action. It interferes directly with viral infectivity and blocks the attachment of HIV-1 particles to target cells, protecting them from virus entry. Analysis of the chemical footprint of anti-HIV activity indicates that HIV-1 inhibition is mediated by multiple polyphenolic compounds with low cytotoxicity and can be separated from other extract components with higher cytotoxicity. Based on our data and its excellent safety profile, we propose that PS extract represents a lead candidate for the development of a scientifically validated herbal medicine for anti-HIV-1 therapy with a mode-of-action different from and complementary to current single-molecule drugs.
PLoS ONE 01/2014; 9(1):e87487. DOI:10.1371/journal.pone.0087487 · 3.23 Impact Factor
"There is an urgent need for new antiretroviral agents for the prevention and treatment of HIV-1. Most of the currently approved HIV drugs target viral enzymes, in particular reverse transcriptase, protease and integrase [1-4]. In contrast, the number of anti-HIV drugs targeting the entry process is more limited. "
[Show abstract][Hide abstract] ABSTRACT: We examined the underlying mechanism of action of the peptide triazole thiol, KR13 that has been shown previously to specifically bind gp120, block cell receptor site interactions and potently inhibit HIV-1 infectivity.
KR13, the sulfhydryl blocked KR13b and its parent non-sulfhydryl peptide triazole, HNG156, induced gp120 shedding but only KR13 induced p24 capsid protein release. The resulting virion post virolysis had an altered morphology, contained no gp120, but retained gp41 that bound to neutralizing gp41 antibodies. Remarkably, HIV-1 p24 release by KR13 was inhibited by enfuvirtide, which blocks formation of the gp41 6-helix bundle during membrane fusion, while no inhibition of p24 release occurred for enfuvirtide-resistant virus. KR13 thus appears to induce structural changes in gp41 normally associated with membrane fusion and cell entry. The HIV-1 p24 release induced by KR13 was observed in several clades of HIV-1 as well as in fully infectious HIV-1 virions.
The antiviral activity of KR13 and its ability to inactivate virions prior to target cell engagement suggest that peptide triazole thiols could be highly effective in inhibiting HIV transmission across mucosal barriers and provide a novel probe to understand biochemical signals within envelope that are involved in membrane fusion.
"While the role of lectins in innate immunity is to recognize and defend against invading pathogens, occasionally through adopting or mimicking carbohydrates of the host, pathogens can gain entry into cells and establish infection. For example, the high mannose shield of the HIV envelope glycoprotein binds to DC- SIGN as the first step in HIV invasion of dendritic cells and some macrophages (Hertje et al., 2010). The same type of interaction with langerin, a C-type lectin restricted to Langerhans cells, transfers HIV to the intracellular Birbeck granules for degradation and clearance (Van Der Vlist and Geijtenbeek, 2010). "
[Show abstract][Hide abstract] ABSTRACT: Recognition of pathogen-associated carbohydrates by a broad range of carbohydrate-binding proteins is central to both adaptive and innate immunity. A large functionally diverse group of mammalian carbohydrate-binding proteins are lectins, which often display calcium-dependent carbohydrate interactions mediated by one or more carbohydrate recognition domains. We report here the application of molecular docking and site mapping to study carbohydrate recognition by several lectins involved in innate immunity or in modulating adaptive immune responses. It was found that molecular docking programs can identify the correct carbohydrate-binding mode, but often have difficulty in ranking it as the best pose. This is largely attributed to the broad and shallow nature of lectin binding sites, and the high flexibility of carbohydrates. Site mapping is very effective at identifying lectin residues involved in carbohydrate recognition, especially with cases that were found to be particularly difficult to characterize via molecular docking. This study highlights the need for alternative strategies to examine carbohydrate-lectin interactions, and specifically demonstrates the potential for mapping methods to extract additional and relevant information from the ensembles of binding poses generated by molecular docking.
Frontiers in Immunology 06/2011; 2:23. DOI:10.3389/fimmu.2011.00023
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.