Polymeric Anti‐HIV Therapeutics

Abstract

The scope of this review is to highlight the application of polymer therapeutics in an effort to curb the transmission and infection of the human immunodeficiency virus (HIV). Following a description of the HIV life cycle, the use of approved antiretroviral drugs that inhibit critical steps in the HIV infection process is highlighted. After that, a comprehensive overview of the structure and inhibitory properties of polymeric anti‐HIV therapeutic agents is presented. This overview will include inhibitors based on polysaccharides, synthetic polymers, dendritic polymers, polymer conjugates as well as polymeric DC‐SIGN antagonists. The review will conclude with a section that discusses the applications of polymers and polymer conjugates as systemic and topical anti‐HIV therapeutics.

Macromolecular Antiviral Agents against Zika, Ebola, SARS, and Other Pathogenic Viruses

“…In turn, HIV-1 is unique in that it incorporates only a few GPs [51,52] and activity of poly mers against HIV-1 is almost trivial and observed for nearly all polymeric inhibitors, here and in numerous inhibitors in prior art. [18,19,53] The HSV-2 surface is intermediate in terms of coverage with GPs [46] and indeed this virus is inhibited by a greater number of polymers in our screen as compared to ZIKV but fewer than HIV-1. Our data indicate that lack of the envelope or an envelope with a dense GP shield makes viruses less susceptible to inhibition by the polymers.…”

“…From the standpoint of structure-activity relationship for the polymers, the first important conclusion from this work is that polysulfonates, strong polyanions which are historically deemed the prime microbicide candidates, [18,53,57] do not make up broad spectrum antiviral materials. Specifically, polymers in this family did not reveal notable inhibitory activity on influenza, SARS, or (except for PSVBS) against ZIKV.…”

Polymeric drugs: Advances in the development of pharmacologically active polymers

“…Unlike small-molecule antivirals that can intervene at different stages of the viral replication (e.g. entry inhibitors, fusion inhibitors, reverse transcriptase inhibitors, integrase inhibitors) [113], antiviral polymeric drugs have been developed mainly based on interfering with the virus interactions with the host cell. Due to the high molecular weight and multivalent binding, polymers exert their antiviral activity by steric shielding of the viral surface or competitive inhibition of the interactions [52,54].…”

“…In addition to dendrimers, negatively charged linear polymers have been also tested as blockers of HIV entry. Sulfonated polymers such as poly(vinyl sulfonate), poly(acrylamido-2-methyl-1-propanesulfonic acid), poly(anetholesulfonate), sulfated poly(vinyl alcohol), and sulfated poly(vinyl alcohol-co-acrylate) all produced effective anti-HIV activity by targeting gp120 (reviewed in [113]). Poly(naphthalene sulfate) (PRO2000) was shown to inhibit HIV-1 entry via binding with soluble CD4 [128].…”

Disulfide Conjugation Chemistry: A Mixed Blessing for Therapeutic Drug delivery?

“…Additionally, maintaining biological activity after conjugation remains a challenge particularly when conjugating polymers to peptides, proteins with macromolecular substrates or proteins that bind substrates requiring a large proportion of its solvent-exposed surface [3,4]. Similarly, permanent polymer conjugation to small molecule inhibitors often results in reduced potencies [5].…”