New Open Access Publication
Mattia Mori , Alessandro Nucci , Maria Chiara Dasso Lang , Nicolas Humbert , Christian Boudier, Francois Debaene , Sarah Sanglier-Cianferani , Marjorie Catala , Patricia Schult-Dietrich ,Ursula Dietrich , Carine Tisné , Yves Mely , and Maurizio Botta
The nucleocapsid protein (NC) is a highly conserved protein in diverse HIV-1 subtypes that plays a central role in virus replication, mainly by interacting with conserved nucleic acid sequences. NC is considered a highly profitable drug target to inhibit multiple steps in the HIV-1 life cycle with just one compound, a unique property not shown by any of the other antiretroviral classes. However, most of NC inhibitors developed so far act through an unspecific and potentially toxic mechanism (zinc ejection) and are mainly being investigated as topical microbicides. In an effort to provide specific NC inhibitors that compete for the binding of nucleic acids to NC, here we combined molecular modeling, organic synthesis, biophysical studies, NMR spectroscopy, and antiviral assays to design, synthesize, and characterize an efficient NC inhibitor endowed with antiviral activity in vitro, a desirable property for the development of efficient antiretroviral lead compounds.