title: Functional and structural characterization of 2-amino-4-phenylthiazole inhibitors of the HIV-1 nucleocapsid protein with antiviral activity.
abstract: 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.
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, Università degli Studi di Siena , via Aldo Moro 2, I-53019 Siena, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Mori
authors.forename: Alessandro
authors.initials: A
authors.lastname: Nucci
authors.forename: Maria Chiara Dasso
authors.initials: MC
authors.lastname: Lang
authors.forename: Nicolas
authors.initials: N
authors.lastname: Humbert
authors.forename: Christian
authors.initials: C
authors.lastname: Boudier
authors.forename: Francois
authors.initials: F
authors.lastname: Debaene
authors.forename: Sarah
authors.initials: S
authors.lastname: Sanglier-Cianferani
authors.forename: Marjorie
authors.initials: M
authors.lastname: Catala
authors.forename: Patricia
authors.initials: P
authors.lastname: Schult-Dietrich
authors.forename: Ursula
authors.initials: U
authors.lastname: Dietrich
authors.forename: Carine
authors.initials: C
authors.lastname: Tisné
authors.forename: Yves
authors.initials: Y
authors.lastname: Mely
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002151:Calorimetry / Q000379:methods; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects / Q000821:virology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D019590:Nucleocapsid Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D019590:Nucleocapsid Proteins; D013844:Thiazoles; C028979:phenthiazamine