Multi-targeting the Entrance Door to Block HIV-1

Borkow, Gadi; Lapidot, Aviva

doi:10.2174/1568005053174645

Cited by 31 publications

(39 citation statements)

References 179 publications

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“…Fusion or entry inhibitors are considered an attractive option, since blocking HIV entry into its target cell leads to suppression of viral infectivity, replication, and the cytotoxicity induced by the virus-cell interaction [4]. Since 2005, only two fusion inhibitors have been approved by the FDA (Enfurtivide and Maravirovic).…”

Section: Introductionmentioning

confidence: 99%

Mode of antiviral action of silver nanoparticles against HIV-1

et al. 2010

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BackgroundSilver nanoparticles have proven to exert antiviral activity against HIV-1 at non-cytotoxic concentrations, but the mechanism underlying their HIV-inhibitory activity has not been not fully elucidated. In this study, silver nanoparticles are evaluated to elucidate their mode of antiviral action against HIV-1 using a panel of different in vitro assays.ResultsOur data suggest that silver nanoparticles exert anti-HIV activity at an early stage of viral replication, most likely as a virucidal agent or as an inhibitor of viral entry. Silver nanoparticles bind to gp120 in a manner that prevents CD4-dependent virion binding, fusion, and infectivity, acting as an effective virucidal agent against cell-free virus (laboratory strains, clinical isolates, T and M tropic strains, and resistant strains) and cell-associated virus. Besides, silver nanoparticles inhibit post-entry stages of the HIV-1 life cycle.ConclusionsThese properties make them a broad-spectrum agent not prone to inducing resistance that could be used preventively against a wide variety of circulating HIV-1 strains.

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Section: Introductionmentioning

confidence: 99%

Mode of antiviral action of silver nanoparticles against HIV-1

et al. 2010

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“…After the virus got attached to CD4 receptor, conformational changes occur to expose the interacting surfaces of chemokine receptors (CCR5/ CXCR4) (Bandres et al, 1998;Guo et al, 2003). Followed by this step gp41 triggers out which fuse the viral and target cell membrane and pour out all the viral material into host cell cytosol (Borkow and Lapidot, 2005;Harrison, 2005).…”

Section: Introductionmentioning

confidence: 99%

Molecular modeling study of HIV-1 gp120 attachment inhibitors

et al. 2011

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The viral glycoprotein 120 (gp120) is a glycoprotein exposed on viral surface. The gp120 is essential for virus entry into cells as it plays a vital role in seeking out specific cell surface receptors for entry. In this article, we performed docking and three-dimensional quantitative structure activity relationship (3D-QSAR) study on a series of 48 indole glyoxamide derivatives as gp120 inhibitors. Docking study revealed that the inhibitor docked deeply into the gp120 cavity rather than Phe43 of cluster of differentiation 4 (CD4). 3D-QSAR methodologies, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) were utilized to rationalize the structural variations with their inhibitory activities. The docked pose of the most potent molecule (43) was used to determine the structures of other molecules. The CoMFA yielded a model with cross-validated correlation coefficient of (q 2 ) 0.73 and non-crossvalidated correlation coefficient of (r 2 ) 0.89 with optimum number of components (N = 3). The CoMSIA models were obtained with the combination of various parameters. Final model was computed with steric, hydrophobic-and hydrogen-bond acceptor (SHA) parameters with reasonable statistics (q 2 = 0.80, r 2 = 0.94 and N = 5). The predictive power of developed CoMFA and CoMSIA models were assessed by test set (nine molecules). The predictive r pred 2 for CoMFA and CoMSIA model was found to be 0.93 and 0.74, respectively. The generated contour maps were plotted onto the gp120 active site to correlate structural variations with their biological activity in protein environment. Contour map analyses showed the importance of 4-F substitution of indole ring, which made essential electronic interaction with the crucial residue (Trp427). The 3D models could explain nicely the structure-activity relationships of indole glyoxamide analogs. This would give proper guidelines to further enhance the activity of novel inhibitors.

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“…For instance, a combination of the HIV triple cocktail therapy with Tannin, a polyphenolic fraction derived from a medicinal herb, has been shown to produce a significant, synergistic and long lasting effect in stabilizing HIV virus propagation by tackling the complex multiple components of HIV-1. Tannin suppresses HIV-1 reverse transcriptase, protease and intergrase activities and blocks virus fusion and virus entry to the host cells [16]. Another typical example is artemisinin, an anti-malarial drug purified from the Chinese medicinal herb Qinghao; its discoverer won the Lasker Award in 2011.…”

Section: Network-based Drug Discovery From Herbsmentioning

confidence: 99%

Network-based drug discovery by integrating systems biology and computational technologies

Leung

Cao²,

Jiang³

et al. 2012

Briefings in Bioinformatics

107

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Network-based intervention has been a trend of curing systemic diseases, but it relies on regimen optimization and valid multi-target actions of the drugs. The complex multi-component nature of medicinal herbs may serve as valuable resources for network-based multi-target drug discovery due to its potential treatment effects by synergy. Recently, robustness of multiple systems biology platforms shows powerful to uncover molecular mechanisms and connections between the drugs and their targeting dynamic network. However, optimization methods of drug combination are insufficient, owning to lacking of tighter integration across multiple ‘-omics’ databases. The newly developed algorithm- or network-based computational models can tightly integrate ‘-omics’ databases and optimize combinational regimens of drug development, which encourage using medicinal herbs to develop into new wave of network-based multi-target drugs. However, challenges on further integration across the databases of medicinal herbs with multiple system biology platforms for multi-target drug optimization remain to the uncertain reliability of individual data sets, width and depth and degree of standardization of herbal medicine. Standardization of the methodology and terminology of multiple system biology and herbal database would facilitate the integration. Enhance public accessible databases and the number of research using system biology platform on herbal medicine would be helpful. Further integration across various ‘-omics’ platforms and computational tools would accelerate development of network-based drug discovery and network medicine.

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Multi-targeting the Entrance Door to Block HIV-1

Cited by 31 publications

References 179 publications

Mode of antiviral action of silver nanoparticles against HIV-1

Mode of antiviral action of silver nanoparticles against HIV-1

Molecular modeling study of HIV-1 gp120 attachment inhibitors

Network-based drug discovery by integrating systems biology and computational technologies

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