Sulfoglycodendrimer Therapeutics for HIV-1 and SARS-CoV-2.

Hexavalent sulfoglycodendrimers (SGDs) are synthesized as mimics of host cell heparan sulfate proteoglycans (HSPGs) to inhibit the early stages in viral binding/entry of HIV-1 and SARS-CoV-2. Using an HIV neutralization assay, the most promising of the seven candidates are found to have sub-micromolar anti-HIV activities. Molecular dynamics simulations are separately implemented to investigate how/where the SGDs interacted with both pathogens. The simulations revealed that the SGDs: 1) develop multivalent binding with polybasic regions within and outside of the V3 loop on glycoprotein 120 (gp120) for HIV-1, and consecutively bind with multiple gp120 subunits, and 2) interact with basic amino acids in both the angiotensin-converting enzyme 2 (ACE2) and HSPG binding regions of the Receptor Binding Domain (RBD) from SARS-CoV-2. These results illustrate the considerable potential of SGDs as inhibitors in viral binding/entry of both HIV-1 and SARS-CoV-2 pathogens, leading the way for further development of this class of molecules as broad-spectrum antiviral agents.

Evaluation of the synthesis of sialic acid-PAMAM glycodendrimers without the use of sugar protecting groups, and the anti-HIV-1 properties of these compounds.

A study was undertaken to evaluate the feasibility of synthesizing six sialic acid-PAMAM glycodendrimers using unprotected sialic acid in as few as 1-4 steps using two different reaction pathways, and to assess the sulfated derivatives for anti-HIV activity. The syntheses were accomplished through either the direct attachment of the sialic acid carboxyl group to amine-terminated PAMAM (a divergent-like approach) using BOP coupling, or by first reacting sialic acid with a polar bifunctional spacer molecule, attaching the sugar-linker to carboxy-terminated PAMAM (a convergent-like approach), and again using BOP-mediated coupling reactions. It was hypothesized that the latter approach would be the most successful method, as any steric congestion between the sialic acid and the PAMAM would be minimized using an intervening polar linker. However, the divergent-like synthesis proved to be the superior method, resulting in 11.4%, 14%, and 28% of the fully substituted generations 0, 1, and 2 sialic acid-PAMAM conjugates, respectively, as compared to 6.4% of only the generation -0.5 sialic acid-linker-PAMAM conjugate for the convergent-like method. Upon sulfation of the four glycodendrimers, binding capabilities to the recombinant HIV protein, gp120, were assessed using an ELISA assay. Compounds that showed promising binding characteristics were then further assessed for inhibition of HIV-1 infection using a well-characterized luciferase reporter gene neutralization assay. The generation 2 sulfated sialic acid-PAMAM glycodendrimer, sulfo-6, bearing 16 sialic acids with 11 sulfate groups incorporated at 4.03% sulfur content by weight, was found to inhibit all four HIV-1 strains tested in the low micromolar range.