Design and Synthesis of DiselenoBisBenzamides (DISeBAs) as Nucleocapsid Protein 7 (NCp7) Inhibitors with anti-HIV Activity

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.