Heparin-Mimicking Sulfonic Acid Polymers as Multitarget Inhibitors of Human Immunodeficiency Virus Type 1 Tat and gp120 Proteins

Abstract

Human immunodeficiency virus (HIV) Tat and gp120 intriguingly share the feature of being basic peptides that, once released by HIV ؉ cells, bind to polyanionic heparan sulfate proteoglycans (HSPGs) on target uninfected cells, contributing to the onset of AIDS-associated pathologies. To identify multitarget anti-HIV prodrugs, we investigated the gp120 and Tat antagonist potentials of a series of polyanionic synthetic sulfonic acid polymers (SSAPs). Surface plasmon resonance revealed that SSAPs inhibit with a competitive mechanism of action the binding of Tat and gp120 to surface-immobilized heparin, an experimental condition that resembles binding to cellular HSPGs. Accordingly, SSAPs inhibited HSPG-dependent cell internalization and the transactivating activity of Tat. Little is known about the binding of free gp120 to target cells. Here, we identified two classes of gp120 receptors expressed on endothelial cells, one of which was consistent with an HSPG-binding, low-affinity/high-capacity receptor that is inhibited by free heparin. SSAPs inhibited the binding of free gp120 to endothelial cells, as well as its capacity to induce apoptosis in the same cells. In all the assays, poly(4-styrenesulfonic acid) (PSS) proved to be the most potent antagonist of Tat and gp120. Accordingly, PSS bound both proteins with high affinity. In conclusion, SSAPs represent an interesting class of compounds that bind both gp120 and Tat and inhibit their HSPG-dependent cell surface binding and pathological effects. As these activities contribute to both AIDS progression and associated pathologies, SSAPs can be considered prototypic molecules for the development of multitarget drugs for the treatment of HIV infection and AIDS-associated pathologies.

Molecular Interaction Studies of HIV-1 Matrix Protein p17 and Heparin

“…To identify the biochemical features of heparin involved in its binding to p17, we exploited a SPR competition assay already used to evaluate the HSPGs antagonist capacity of various polyanionic compounds (20). As shown in Fig.…”

“…Biochemical Characterization of p17/Heparin Interaction-SPR was exploited to evaluate the capacity of p17 to bind sensorchip-immobilized heparin, a model that mimics the binding of proteins to cell surface-associated HSPGs (20). p17 interacts with immobilized heparin but not with streptavidin ( Fig.…”

“…HIV-infected cells release Tat, gp120, and p17 proteins that, acting in a cytokine-like manner, target uninfected leukocytes (56,57), neurons (58 -60), and endothelial cells (20,60,61) inducing various biological effects that, in turn, favor viral spread and the onset of AIDS-associated diseases. Some of these effects depend on the interaction of the viral proteins with HSPGs expressed on the surface of target cells (18,52,62), making this class of receptors a promising nodal targets for the development of "multitarget" anti-HIV drugs.…”

Long Pentraxin-3 Inhibits FGF8b-Dependent Angiogenesis and Growth of Steroid Hormone–Regulated Tumors

“…Activated/deactivated Fc2 flow cell was used as a reference cell and for blank subtraction. (ii) Size-defined heparin (13.6 kDa) was biotinylated on its reducing end as described previously (14), and a flow cell of a CM3 sensor chip was activated with streptavidin. Then, biotinylated heparin was allowed to react with the streptavidin-coated sensor chip.…”

Removing human immunodeficiency virus (HIV) from human blood using immobilized heparin

“…Potential advantages of this concept are: (i) eliminating the systemic spread of treatment chemicals; (ii) that heparin binds HIV-1's Tat (transactivating factor) and gp120 (surface protein) which are responsible for AIDS-associated pathologies (Bugatti et al 2007); and (iii) using readily prepared starting materials.…”