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

• Published in: Bioconjugate chemistry 2018-05, Vol.29 (5), p.1584-1594
• Main Authors: Guerrero-Beltran, Carlos, Rodriguez-Izquierdo, Ignacio, Serramia, Ma Jesus, Araya-Durán, Ingrid, Márquez-Miranda, Valeria, Gomez, Rafael, de la Mata, Francisco Javier, Leal, Manuel, González-Nilo, Fernando, Muñoz-Fernández, M. Angeles
• Format: Article
• Language: English
• Subjects: Anions - chemistry; Anions - pharmacology; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Biocompatibility; CCR5 protein; CD4 antigen; CD4 Antigens - metabolism; Cell fusion; Cell Line; Cell lines; Coding; CXCR4 protein; Dendrimers; Dendrimers - chemistry; Dendrimers - pharmacology; Glycoprotein gp120; HIV; HIV Envelope Protein gp120 - metabolism; HIV Infections - drug therapy; HIV Infections - metabolism; HIV-1 - drug effects; HIV-1 - physiology; Human immunodeficiency virus; Humans; Models, Molecular; Molecular chains; Molecular modelling; Proteins; Silanes - chemistry; Silanes - pharmacology; Syncytia; Virus Internalization - drug effects; Viruses
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.8b00106

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.