Polyanionic Drugs and Viral Oncogenesis: a Novel Approach to Control Infection, Tumor-associated Inflammation and Angiogenesis

Abstract

Polyanionic macromolecules are extremely abundant both in the extracellular environment and inside the cell, where they are readily accessible to many proteins for interactions that play a variety of biological roles. Among polyanions, heparin, heparan sulfate proteoglycans (HSPGs) and glycosphingolipids (GSLs) are widely distributed in biological fluids, at the cell membrane and inside the cell, where they are implicated in several physiological and/or pathological processes such as infectious diseases, angiogenesis and tumor growth. At a molecular level, these processes are mainly mediated by microbial proteins, cytokines and receptors that exert their functions by binding to HSPGs and/or GSLs, suggesting the possibility to use polyanionic antagonists as efficient drugs for the treatment of infectious diseases and cancer. Polysulfated (PS) or polysulfonated (PSN) compounds are a heterogeneous group of natural, semi-synthetic or synthetic molecules whose prototypes are heparin and suramin. Different structural features confer to PS/PSN compounds the capacity to bind and inhibit the biological activities of those same heparin-binding proteins implicated in infectious diseases and cancer. In this review we will discuss the state of the art and the possible future development of polyanionic drugs in the treatment of infectious diseases and cancer.

BSA conjugates bearing multiple copies of the basic domain of HIV-1 Tat: Prototype for the development of multitarget inhibitors of extracellular Tat

“…In effect, the basic domain of Tat has been exploited to develop polyanionic compounds, mainly studied for their potential as extracellular Tat-antagonists (Rusnati and Presta, 2002b;Rusnati et al, 2005) or microbicides . Unfortunately, these compounds usually lack specificity and cell permeability and suffer from high toxicity and anticoagulant activity (Urbinati et al, 2008).…”

Heparan Sulfate Proteoglycans: A Multifaceted Target for Novel Approaches in Antiviral Drug Discovery

“…As a result, a long list of heparin-derivatives, synthetic polyanionic molecules, plant and marine polysaccharides and biotechnological heparins have been obtained that exert a potent antiviral activity in vitro [5,6,9,10]. However, the only three polyanionic anti-HIV-1 microbicides that reached phase III clinical trial (namely the polysulfonated PRO2000 and the polysulfated carraguard and cellulose Ushercell) turned out to be not efficacious against vaginal HIV-1 transmission or even to increase the rate of infection [12][13][14].…”

“…Many viruses (including HIV-1, HSV, HPV and RSV) exploit heparan sulfate proteoglycans (HSPGs) as attachment receptors [5][6][7]. HSPGs are expressed on the surface of almost all eukaryotic cell types and consist of a core protein and unbranched anionic chains composed of repeating disaccharides units (sulfated uronic acid and hexosamine residues) [8].…”

“…Heparin binds to those same enzymes, growth factors, cytokines and viral proteins that use HSPGs as receptors [5,6,9,10], acting as a potent HSPG-antagonist. However, due to its strong anticoagulant activity, heparin cannot be used as an antiviral drug [11], prompting a series of studies aimed at identifying heparinlike molecules endowed with a more favorable therapeutic window [5,6,9,10]. To this aim, different approaches have been so far applied, including chemical modification of heparin (selective desulfation, tailoring of the saccharidic chain length, modification of the backbone flexibility), enzymatic sulfation of unsulfated glycosaminoglycans, rational design of synthetic molecules, generation of heparin nanoassemblies and screening of library of natural compounds.…”

“…The parental compound suramin is a polysulfonated naphthylurea that contains eight benzene rings, four of which are fused in pairs (naphthalene groups), four amide groups in addition to the one of urea and six sulfonated groups. Starting from suramin, several derivatives have been chemically synthesized to be used for the treatment of several infectious diseases [5,6,9,10].…”