Novel monocyclam derivatives as HIV entry inhibitors: Design, synthesis, anti-HIV evaluation, and their interaction with the CXCR4 co-receptor

Sofia Pettersson, Violeta I. Pérez-Nueno, Maria Pau Mena, Bonaventura Clotet, José A. Esté, José I. Borrell, Jordi Teixidó

Producción científica: Artículo en revista indizadaArtículorevisión exhaustiva

20 Citas (Scopus)

Resumen

The CXCR4 receptor has been shown to interact with the human immunodeficiency virus (HIV) envelope glycoprotein gp120, leading to fusion of viral and cell membranes. Therefore, ligands that can attach to this receptor represent an important class of therapeutic agents against HIV, thus inhibiting the first step in the cycle of viral infection: the virus-cell entry/ fusion. Herein we describe the in silico design, synthesis, and biological evaluation of novel monocyclam derivatives as HIV entry inhibitors. In vitro activity testing of these compounds in cell cultures against HIV strains revealed EC50 values in the low micromolar range without cytotoxicity at the concentrations tested. Docking and molecular dynamics simulations were performed to predict the binding interactions between CXCR4 and the novel monocyclam derivatives. A binding mode of these compounds is proposed which is consistent with the main existing site-directed mutagenesis data on the CXCR4 coreceptor. Moreover, molecular modeling comparisons were performed between these novel monocyclams, previously reported non-cyclam compounds from which the monocyclams are derived, and the well-known AMD3100 bicyclam CXCR4 inhibitors. Our results suggest that these three structurally diverse CXCR4 inhibitors bind to overlapping but not identical amino acid residues in the transmembrane regions of the receptor.

Idioma originalInglés
Páginas (desde-hasta)1272-1281
Número de páginas10
PublicaciónChemMedChem
Volumen5
N.º8
DOI
EstadoPublicada - 2 ago 2010

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