HIV-1 X4 Activities of Polycationic “Viologen” Based Dendrimers by Interaction with the Chemokine Receptor CXCR4: Study of Structure–Activity Relationship

Abstract

A series of "viologen" based dendrimers with polycationic scaffold carrying 10, 18, 26, 42, and 90 charges per molecule were used to determine the structure-activity relationship (SAR) with regard to HIV-1 inhibitory activity. The studies involved five compounds with a high activity against HIV-1 already utilized in our previous study (1) and five new dendrimers. Such dendrimers block HIV-1 entry into the cell, indicating that they bind to HIV-1 surface proteins and/or on the host cell receptors required for entry. The increasing positive character of dendrimers leads to more cytotoxicity. The 10 charges dendrimers (1, 6) have less influence on the cell viability but low inhibition of the binding of the CXCR4 mAb clone 1D9. Thus, dendrimers with 18 charges (2, 7) are the most promising CXCR4 imaging probes. We report the design, synthesis, and biological activity of new HIV-1 inhibitors that are conceptually distinct from those of the existing HIV-1 inhibitors.

Exploring ‘new’ bioactivities of polymers at the nano–bio interface

“…Similarly, another set of polycations, 'viologen' (Nalkylated 4,4 0 -bipyridinium)-based dendrimers, were designed to modulate immune cells [14,15]. Some viologen-based polycation macromolecules, those with 10-90 charges per molecule, can directly bind the chemokine receptor CXCR4 [15] and exert activity against the human immunodeficiency virus type 1 (HIV-1) in primary human cell cultures [14]. Cationic polymers that can interact with antigens or receptors have emerged as promising candidates for therapeutic agents with broad applications.…”

Polymeric Anti‐HIV Therapeutics

“…[88,89] Two types of dendritic viologens, namely 'comb-branched' (23) and 'spheroidal' (24), were investigated for their antiviral properties. The spheroidal viologen dendrimers (24) were shown to be more effective than comb-branched dendrimers.…”

“…In a subsequent study, Asaftei et al proposed that the thymine end-capped dendrimer viologens have a dual advantage. [89] Firstly, the polycationic scaffold binds to the heparan sulfate present on the surface of T-cell lines and secondly, the thymine moieties presented on the periphery of the dendrimers are capable of hydrogen bonding with negatively charged residues on CXCR4. However, the thymine functionalized viologen dendrimers exhibited similar anti-HIV-1 efficacies to the ethyl functionalized counterparts when using MT-4 cells and lower efficacies when infectivity was assayed with PBMC cells.…”

“…However, the thymine functionalized viologen dendrimers exhibited similar anti-HIV-1 efficacies to the ethyl functionalized counterparts when using MT-4 cells and lower efficacies when infectivity was assayed with PBMC cells. [89] Cytotoxicity, as assessed by the MTT assay in MT-4 cells and PBMC, showed that the 1 st generation 'comb-branched' viologen dendrimers (23) exhibited a higher selectivity than the 2 nd generation counterparts. Similarly, 1 st generation 'spheroidal' viologen dendrimers (24) exhibited a higher selectivity than the 3 rd generation dendrimers.…”

Antiviral mechanism of polyanionic carbosilane dendrimers against HIV-1

“…18,19 Moreover, polycationic "viologen"-based dendrimers have also shown anti-HIV activity by interaction with the chemokine receptor CXCR4. 20 Other dendrimers have presented dual acting mechanism such as four-generation polyamidoamine (PAMAM) branchednaphthalene disulfonic surface groups ended SPL2923 18 or polysulfonated dendrimer BRI2923, 21 which inhibited not only HIV-1 entry but also later steps (reverse transcriptase/ integrase) of the viral replicative cycle. Multivalent dendrimeric compounds containing carbohydrates expressed on immune cells such as globotriose and 3′-sialyl lactose glycosphingolipids also inhibited infection of HIV-1 targeting HIV entry to its target cells, 22 whereas multivalent glycodendrimeric compounds were shown to prevent HIV transmission via DC-SIGN in dendritic cells (DCs).…”