@article{68b335836bc145eab216b7de5f3a4eae,
title = "Identification of 2-(4-N,N-Dimethylaminophenyl)-5-methyl-1-phenethyl-1H-benzimidazole targeting HIV-1 CA capsid protein and inhibiting HIV-1 replication in cellulo",
abstract = "The capsid (CA) subunit of the HIV-1 Gag polyprotein is involved in several steps of the viral cycle, from the assembly of new viral particles to the protection of the viral genome until it enters into the nucleus of newly infected cells. As such, it represents an interesting therapeutic target to tackle HIV infection. In this study, we screened hundreds of compounds with a low cost of synthesis for their ability to interfere with Gag assembly in vitro. Representatives of the most promising families of compounds were then tested for their ability to inhibit HIV-1 replication in cellulo. From these molecules, a hit compound from the benzimidazole family with high metabolic stability and low toxicity, 2-(4-N,N-dimethylaminophenyl)-5-methyl-1-phenethyl-1H-benzimidazole (696), appeared to block HIV-1 replication with an IC50 of 3 µM. Quantitative PCR experiments demonstrated that 696 does not block HIV-1 infection before the end of reverse transcription, and molecular docking confirmed that 696 is likely to bind at the interface between two monomers of CA and interfere with capsid oligomerization. Altogether, 696 represents a promising lead molecule for the development of a new series of HIV-1 inhibitors.",
keywords = "Benzimidazole, CA, Capsid, HIV-1, Inhibitor, p24",
author = "Guzm{\'a}n Alvarez and {van Pul}, Lisa and Xavier Robert and Zoraima Art{\'i}a and {van Nuenen}, {Ad C.} and Mathieu Long and Natalia Sierra and Williams Porcal and Kootstra, {Neeltje A.} and Christophe Guillon",
note = "Funding Information: The authors thank R.A. Gruters for helpful advices, M. Summers for the gift of the CA expression plasmid and C. Coiffier and B. Verrier for the gift of recombinant HIV-1 CA for affinity assays. We also thank the SFR Biosciences (UMS3444/CNRS, US8/Inserm, ENS de Lyon, UCBL) PSF facility, in particular R. Montserret and C. Freton for assistance with ITC and MST, respectively. This work was supported in part by CSIC (Comisi{\'o}n Sectorial de Investigaci{\'o}n Cient{\'i}fica) programa iniciaci{\'o}n a la investigaci{\'o}n 2017 number ID275, and by the Franco-Uruguayan Ecos-Sud program (U14S01). ML is recipient from a doctoral fellowship from the “Minist{\`e}re de l{\textquoteright}Enseignement Sup{\'e}rieur et de la Recherche”. Funding Information: This work was supported in part by CSIC (Comisi{\'o}n Sectorial de Investigaci{\'o}n Cient{\'i}fica) programa iniciaci{\'o}n a la investigaci{\'o}n 2017 number ID275, and by the Franco-Uruguayan Ecos-Sud program (U14S01). Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
day = "1",
doi = "https://doi.org/10.1186/s40360-022-00581-7",
language = "English",
volume = "23",
journal = "BMC pharmacology & toxicology",
issn = "2050-6511",
publisher = "BioMed Central Ltd.",
number = "1",
}