The rise and fall of polyanionic inhibitors of the human immunodeficiency virus type 1
ABSTRACT Infection by the human immunodeficiency virus type 1 (HIV-1) is an ordered, multistep process involving binding and entry, reverse transcription, integration, viral gene transcription, translation, processing, and finally assembly. Numerous therapeutic and preventive compounds, which are currently available for clinical use or are under preclinical and clinical development, act on at least one of these steps. Polyanionic HIV-1 inhibitors comprise a family of compounds that are generally considered entry inhibitors. The main mechanism of anti-HIV-1 activity associated with these compounds involves electrostatic interactions with HIV-1 glycoprotein 120 that ultimately prevent binding of the virus to target cells. A number of these compounds have been considered for systemic use and for use as microbicides, which are products designed to prevent sexual HIV-1 transmission. These compounds have been studied extensively using in vitro assays of activity, cytotoxicity, and mechanism of action, ex vivo models of HIV-1 transmission, and animal models of in vivo efficacy and toxicity. Three of these polyanionic compounds - cellulose sulfate, carrageenan, and PRO 2000 - were advanced into clinical trials of microbicide safety and efficacy. Although phase I and phase II clinical trials showed these compounds to be safe and well tolerated, none of the phase III trials provided any evidence that these compounds were effective against heterosexual HIV-1 transmission. Furthermore, clinical and in vitro results suggest enhancement of HIV-1 infection in the presence of polyanionic compounds. We discuss the preclinical development of polyanionic HIV-1 inhibitors, the clinical trials of polyanionic compounds used systemically and as topical vaginal microbicides, and the prospects for the future development of these compounds as inhibitors of HIV-1 infection.
- SourceAvailable from: Justin O. Zoppe
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- "Polyanionic compounds and multivalent nanoparticles carry - ing sulfate or phenyl sulfonate groups are highly effective viral inhibitors ( Baram - Pinto et al . , 2009 , 2010 ; Di Gianvincenzo et al . , 2010 ; Pirrone et al . , 2011 ; Yamamoto et al . , 1991 ) . In previous work , we have shown that CNCs carrying multivalent displays of sulfate or phenyl sulfonate groups inhibited alphavirus infections ( Zoppe et al . , 2014 ) . The synthesis of CNCs carrying phenyl sulfonate ligands involved laborious solvent exchange steps and multi - step synthesis in organic me"
ABSTRACT: We report a facile aqueous procedure to create multivalent displays of sulfonated ligands on CNCs for future applications as viral inhibitors. CNCs were decorated with model compounds containing sulfonate groups via reactions of epoxides and isothiocyanates with amines under alkaline conditions. At first, surface sulfate groups of CNCs were hydrolytically cleaved by alkaline hydrolysis to increase the number of available surface hydroxyls. Success of desulfation was confirmed via dynamic light scattering (DLS), zeta potential measurements and thermogravimetric analysis (TGA). CNC surface hydroxyl groups were then activated with epichlorohydrin before subsequent reactions. As proof of concept toward aqueous pathways for functionalizing nanoparticles with sulfonated ligands, 3-chloro-2-hydroxy-1-propanesulfonic acid sodium salt hydrate (CPSA) and 4-sulfophenyl isothiocyanate sodium salt monohydrate (4-SPITC) were chosen as model compounds to react with homobifunctional 2,2'-(ethylenedioxy)bis(ethylamine) (EBEA) molecular spacer. The approaches presented are not only applicable to polysaccharide nanocrystals, but also other classes of polymeric and inorganic substrates presenting surface hydroxyl groups, as in the case of poly(2-hydroxyethyl methacrylate) (PHEMA), silica or glass. CNCs carrying sulfonated ligands were characterized by ATR-FTIR and UV-vis spectroscopy. Surface chemical compositions of desired elements were determined via X-ray photoelectron spectroscopy (XPS). We anticipate that with these facile aqueous procedures as the proof of concept, a diverse library of target-specific functionalities can be conjugated to CNCs for applications in nanomedicine, especially related to viral inhibition. Copyright © 2015 Elsevier Ltd. All rights reserved.Carbohydrate Polymers 03/2015; 126:23-31. DOI:10.1016/j.carbpol.2015.03.005 · 4.07 Impact Factor
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- "In addition to suramin, dextran sulfate, and heparin, which were considered for systemic use, this includes many other sulfated/acidic compounds such as carrageenan, cellulose sulfate, polystyrene sulfonate or maleic acid, naphthalene sulfonate, and cellulose acetate phthalate, developed as anti HIV-1 microbicides. Unfortunately, none of these compounds proved to be effective in vivo presumably due to poor availability, toxicity, sequestration by plasma proteins, induced reduction in epithelial integrity and concomitant increases in permeability to HIV-1 particles (67, 68). Their variability, in terms of molecular weights and degrees of sulfation also made them difficult to standardize. "
ABSTRACT: By targeting cells that provide protection against infection, HIV-1 causes acquired immunodeficiency syndrome. Infection starts when gp120, the viral envelope glycoprotein, binds to CD4 and to a chemokine receptor usually CCR5 or CXCR4. As many microorganisms, HIV-1 also interacts with heparan sulfate (HS), a complex group of cell surface associated anionic polysaccharides. It has been thought that this binding, occurring at a step prior to CD4 recognition, increases infectivity by pre-concentrating the virion particles at the cell surface. Early work, dating from before the identification of CCR5 and CXCR4, showed that a variety of HS mimetics bind to the gp120 V3 loop through electrostatic interactions, compete with cell surface associated HS to bind the virus and consequently, neutralize the infectivity of a number of T cell line-adapted HIV-1 strains. However, progress made to better understand HIV-1 attachment and entry, coupled with the recent identification of additional gp120 regions mediating HS recognition, have considerably modified this view. Firstly, the V3 loop from CXCR4-using viruses is much more positively charged compared to those using CCR5. HS inhibition of cell attachment is thus restricted to CXCR4 using viruses (such as T cell line-adapted HIV-1). Secondly, studies aiming at characterizing the gp120/HS complex revealed that HS binding was far more complex than previously thought: in addition to the V3 loop of CXCR4 tropic gp120, HS interacts with several other cryptic areas of the protein, which can be induced upon CD4 binding, and are conserved amongst CCR5 and CXCR4 viruses. In view of these data, this review will detail the present knowledge on HS binding to HIV-1, with regards to attachment and entry processes. It will discuss the perspective of targeting the gp120 coreceptor binding site with HS mimetic compounds, a strategy that recently gave rise to entry inhibitors that work in the low nM range, independently of coreceptor usage.Frontiers in Immunology 11/2013; 4:385. DOI:10.3389/fimmu.2013.00385
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- "Cell surface glycosphingolipids such as galactosylceramide can act as a receptor for the HIV gp120 and facilitate HIV entry in the absence of CD4 receptors . On the other hand, a variety of linear sulfated polysaccharides have shown the ability to inhibit HIV entry in vitro although they were unsuccessful in clinical trials . In view of this, it was hypothesized that Fig. 4. Salient features of various nano-architectures. "
ABSTRACT: a b s t r a c t Successful treatment and control of HIV/AIDS is one of the biggest challenges of 21st century. More than 33 million individuals are infected with HIV worldwide and more than 2 million new cases of HIV infection have been reported. The situation demands development of effective prevention strategies to control the pandemic of AIDS. Due to lack of availability of an effective HIV vaccine, antiretroviral drugs and nucleic acid therapeutics like siRNA have been explored for HIV prophylaxis. Clinical trials shave shown that antiretroviral drugs, tenofovir and emtricitabine can offer some degree of HIV prevention. However, complete prevention of HIV infection has not been achieved yet. Nanotechnology has brought a paradigm shift in the diagnosis, treatment and prevention of many diseases. The current review dis-cusses potential of various nanocarriers such as dendrimers, polymeric nanoparticles, liposomes, lipid nanocarriers, drug nanocrystals, inorganic nanocarriers and nanofibers in improving efficacy of various modalities available for HIV prophylaxis.Biomaterials 05/2013; 34(26). DOI:10.1016/j.biomaterials.2013.05.012 · 8.56 Impact Factor