title: Design and Synthesis of DiselenoBisBenzamides (DISeBAs) as Nucleocapsid Protein 7 (NCp7) Inhibitors with anti-HIV Activity.
abstract: The interest in the synthesis of Se-containing compounds is growing with the discovery of derivatives exhibiting various biological activities. In this manuscript, we have identified a series of 2,2'-diselenobisbenzamides (DISeBAs) as novel HIV retroviral nucleocapsid protein 7 (NCp7) inhibitors. Because of its pleiotropic functions in the whole viral life cycle and its mutation intolerant nature, NCp7 represents a target of great interest which is not reached by any anti-HIV agent in clinical use. Using the diselenobisbenzoic scaffold, amino acid, and benzenesulfonamide derivatives were prepared and biologically profiled against different models of HIV infection. The incorporation of amino acids such as glycine and glutamate into DISeBAs 7 and 8 resulted in selective anti-HIV activity against both acutely and chronically infected cells as well as an interesting virucidal effect. DISeBAs demonstrated broad antiretroviral activity, encompassing HIV-1 drug-resistant strains including clinical isolates, as well as simian immunodeficiency virus (SIV). Time of addition experiments, along with the observed dose dependent inhibition of the Gag precursor proper processing, confirmed that their mechanism of action is based on NCp7 inhibition.
authors.affiliation: Department of Pharmaceutical Sciences, Group of Catalysis and Organic Green Chemistry, University of Perugia , Via del Liceo 1, Perugia 06100, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Sancineto
authors.affiliation: Department of Pharmaceutical Sciences, Group of Catalysis and Organic Green Chemistry, University of Perugia , Via del Liceo 1, Perugia 06100, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Mariotti
authors.affiliation: Department of Pharmaceutical Sciences, Group of Catalysis and Organic Green Chemistry, University of Perugia , Via del Liceo 1, Perugia 06100, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Bagnoli
authors.affiliation: Department of Pharmaceutical Sciences, Group of Catalysis and Organic Green Chemistry, University of Perugia , Via del Liceo 1, Perugia 06100, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Marini
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia , Via del Liceo 1, Perugia 06100, Italy.
authors.forename: Jenny
authors.initials: J
authors.lastname: Desantis
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia , Via del Liceo 1, Perugia 06100, Italy.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Iraci
authors.affiliation: Department of Pharmaceutical Sciences, Group of Catalysis and Organic Green Chemistry, University of Perugia , Via del Liceo 1, Perugia 06100, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Santi
authors.affiliation: Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven , B-3000 Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia , Via del Liceo 1, Perugia 06100, Italy.
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D007532:Isoleucine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D016566:Organoselenium Compounds / Q000737:chemistry* / Q000494:pharmacology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects; D013329:Structure-Activity Relationship; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors*
chemical_list: D019380:Anti-HIV Agents; D001549:Benzamides; C071884:NCP7 protein, Human immunodeficiency virus 1; D016566:Organoselenium Compounds; D054301:gag Gene Products, Human Immunodeficiency Virus; D007532:Isoleucine; D018698:Glutamic Acid; D005998:Glycine