TY - JOUR
T1 - Anionic Carbosilane Dendrimers Destabilize the GP120-CD4 Complex Blocking HIV-1 Entry and Cell to Cell Fusion
AU - Guerrero-Beltran, Carlos
AU - Rodriguez-Izquierdo, Ignacio
AU - Serramia, Ma Jesus
AU - Araya-Durán, Ingrid
AU - Márquez-Miranda, Valeria
AU - Gomez, Rafael
AU - De La Mata, Francisco Javier
AU - Leal, Manuel
AU - González-Nilo, Fernando
AU - Muñoz-Fernández, M. Angeles
N1 - Funding Information:
This work has been (partially) funded by the RD12/0017/0037, RD16/0025/0019, projects as part of the Accioń Estrateǵ ica en Salud, Plan Nacional de Investigacioń Cientifí ca, Desarrollo e Innovacioń Tecnologića (2008−2011; 2013−2016) and cofinanced by the Instituto de Salud Carlos III (Subdireccioń General de Evaluacion)́ and Fondo Europeo de Desarrollo Regional (FEDER), RETIC PT13/0010/0028, Fondo de Inves-tigacion Sanitaria (FIS) (grant number PI16/01863), CYTED 214RT0482, EPIICAL Project and MINECO CTQ-2014-54004-P. CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008−2011, Iniciativa Ingenio 2010, the Consolider Program, and CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund.
Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/5/16
Y1 - 2018/5/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047260448&partnerID=8YFLogxK
U2 - 10.1021/acs.bioconjchem.8b00106
DO - 10.1021/acs.bioconjchem.8b00106
M3 - Article
AN - SCOPUS:85047260448
SN - 1043-1802
VL - 29
SP - 1584
EP - 1594
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 5
ER -
