Heparin-mimicking sulfonic acid polymers as multitarget inhibitors of HIV-1 Tat and gp120 proteins

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.