Anionic Carbosilane Dendrimers Destabilize the GP120-CD4 Complex Blocking HIV-1 Entry and Cell to Cell Fusion

Abstract

Cell-to-cell transmission is the most effective pathway for the spread of human immunodeficiency virus (HIV-1). Infected cells expose virus-encoded fusion proteins on their surface as a consequence of HIV-1 replicative cycle that interacts with noninfected cells through CD4 receptor and CXCR4 coreceptor leading to the formation of giant multinucleated cells known as syncytia. Our group previously described the potent activity of dendrimers against CCR5-tropic viruses. Nevertheless, the study of G1-S4, G2-S16, and G3-S16 dendrimers in the context of X4-HIV-1 tropic cell-cell fusion referred to syncytium formation remains still unknown. These dendrimers showed a suitable biocompatibility in all cell lines studied and our results demonstrated that anionic carbosilane dendrimers G1-S4, G2-S16, and G3-S16 significantly inhibit the X4-HIV-1 infection, as well as syncytia formation, in a dose dependent manner. We also demonstrated that G2-S16 and G1-S4 significantly reduced syncytia formation in HIV-1 Env-mediated cell-to-cell fusion model. Molecular modeling and in silico models showed that G2-S16 dendrimer interfered with gp120-CD4 complex and demonstrated its potential use for a treatment.

G2-S16 dendrimer microbicide does not interfere with the vaginal immune system

“…G2-S16 dendrimer has been demonstrated to protect against HIV-1 infection when used as prophylactic treatment both in vitro and in vivo, but the mechanism of this protection remains controversial. Computational modeling assays show that it disrupts the union of the virus to the host cell, but they show that it could bind to residues in both the viral gp120 and the CD4 cellular receptor [40]. The cytometry assays performed here show that G2-S16 does not block the binding of antibodies to CD4 receptor, and thus suggest that it does not block the binding of the virus either.…”

“…G2-S16 has been proven to block HIV infection in multiple cell lines and human primary blood cells Chonco et al [19]. This dendrimer inhibits infection even in the presence of semen, a known infection enhancer [17, 39], as well as the cell-to-cell transmission and syncytium formation [40]. On the other hand, the biosafety of this nanocompound has been tested not only in vitro but also ex vivo and in vivo [19, 20, 38].…”

Emergence of Nanotechnology to Fight HIV Sexual Transmission: The Trip of G2-S16 Polyanionic Carbosilane Dendrimer to Possible Pre-Clinical Trials

“…We studied different combinations with actual antiviral compounds, G2-S16 dendrimer showed good compatibility with either maraviroc, tenofovir, or a combination of both [58,101,102]. Molecular modeling dynamics simulations of G2-S16 PCD interaction with gp120 and CD4 confirmed that, although G2-S16 PCD binds to CD4 receptor at important areas for gp120/CD4 and gp120/CCR5 or CXCR4 docking, computational results indicated a significantly higher binding affinity in the case of the G2-S16 PCD/gp120 complex [103].…”

High Preventive Effect of G2-S16 Anionic Carbosilane Dendrimer against Sexually Transmitted HSV-2 Infection

“…Currently, the development of new microbicides revolves heavily around the use of nanotechnology, as it provides a set of state-of-the-art tools to generate effective and safe microbicides against a wide array of infections [37,38]. Particularly, as aforementioned, dendrimers have been demonstrated to present a broad range of applications, mainly in nanomedicine [9,39], and they have a high relevance as antiviral agents against a wide array of viruses [40][41][42][43][44][45]. One of the main problems related to the microbicides is that, despite the great results obtained in vitro and in vivo, the last steps of the clinical trials usually fail, so the preclinical assessment must be more exhaustive.…”