NCp7: targeting a multitask protein for next-generation anti-HIV drug development part 2. Noncovalent inhibitors and nucleic acid binders

Abstract

Nucleocapsid protein 7 (NCp7) represents a viable target not yet reached by the currently available antiretrovirals. It is a small and highly basic protein, which is essential for multiple stages of the viral replicative cycle, with its structure preserved in all viral strains, including clinical isolates. NCp7 can be inhibited covalently, noncovalently and by shielding the nucleic acid (NA) substrates of its chaperone activity. Although covalent NCp7 inhibitors have already been detailed in the first part of this review series, the focus here is based on noncovalent and NA-binder inhibitors and on the analysis of the NCp7 3D structure to deliver fruitful insights for future drug design strategies.

Anti-tubercular profile of new selenium-menadione conjugates against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain and multidrug-resistant clinical isolates

“…Notably, many studies have shown the potential applications of selenium compounds for the treatment of infectious diseases. The antimicrobial efficacy of selenium compounds has been tested against a great variety of microorganisms, demonstrating their activity as antibacterial [ 22 ], antifungal [ 23 ], antiviral [ 24 ] and antiparasitic agents [ 25 ]. Ebselen ( 1 ) is the most well-known and well-studied seleno-derivative, especially for its antioxidant effects, GPx-like activity [ 26 ] and antimicrobial activity [ 27 ].…”

How HIV-1 Gag Manipulates Its Host Cell Proteins: A Focus on Interactors of the Nucleocapsid Domain

“…Furthermore, as the NC domain is a highly conserved region [372], it represents an ideal target to develop compounds inhibiting HIV-1 and, more specifically, viral assembly. Several inhibitors have been studied over the past few years and their potential therapeutic effects against HIV-1 have been recently reviewed [373,374]. Targeting the late phase of the HIV-1 cell cycle and especially the Gag-cellular proteins interactome represents a promising challenge for the development of new drugs.…”

Investigation of the Pentathiepin Functionality as an Inhibitor of Feline Immunodeficiency Virus (FIV) via a Potential Zinc Ejection Mechanism, as a Model for HIV Infection

“…There are two methods of NCp inhibition: one is to compete with the nucleic acid binding site, the other is to interfere directly with the zinc finger structure via zinc ejection. Both approaches have shown promise; however, we chose to use the permanent irreversible ejection of the structural Zn 2+ ion from the viral protein.…”

“…[16][17][18] The NCp is an attractive drug target, as it has been demonstratedt ob emutation resistant,a nd inhibition leads to noninfectious virions. [19] There are two methods of NCp inhibition:o ne is to compete with the nucleic acid binding site, [20,21] the other is to interfere directly with the zinc finger structure via zinc ejection. Both approachesh ave shown promise; however,w ec hose to use the permanent irreversible ejection of the structural Zn 2 + ion from the viral protein.…”