Heparin-mimicking sulfonic acid polymers as multitarget inhibitors of human immunodeficiency virus type 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.
Bugatti
Antonella
A
General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Brescia, Italy.
Urbinati
Chiara
C
Ravelli
Cosetta
C
De Clercq
Erik
E
Liekens
Sandra
S
Rusnati
Marco
M
D053148:Caspase 3 / Q000378:metabolism; D002461:Cell Line, Transformed; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000235:genetics; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D016325:HIV Long Terminal Repeat; D015497:HIV-1; D006367:HeLa Cells; D006493:Heparin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D018716:Molecular Mimicry; D015394:Molecular Structure; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000378:metabolism; D011485:Protein Binding; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D015699:HIV Envelope Protein gp120; D011108:Polymers; D011355:Prodrugs; D013451:Sulfonic Acids; D054322:tat Gene Products, Human Immunodeficiency Virus; D049452:Green Fluorescent Proteins; D006493:Heparin; D005982:Glutathione Transferase; D053148:Caspase 3