Probing Mercaptobenzamides as HIV Inactivators via Nucleocapsid Protein 7

Abstract

Human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein 7 (NCp7), a zinc finger protein, plays critical roles in viral replication and maturation and represents an attractive target for drug development. However, development of drug-like molecules that inhibit NCp7 has been a significant challenge. In this report, a series of novel 2-mercaptobenzamide prodrugs have been investigated for anti-HIV activity in the context of NCp7 inactivation. The molecules are synthesized from the corresponding thiosalicylic acids, and they are all crystalline solids and stable at room temperature. Derivatives with a range of amide side chains and aromatic substituents were synthesized and screened for anti-HIV activity. Wide ranges of antiviral activity were observed, with IC50 values ranging from 1 to 100 μM depending on subtle changes to the substituents on the aromatic ring and the sidechain. Results from these structure-activity relationships were fit to a probable mode of intracellular activation and interaction with NCp7 to explain variations in antiviral activity. Our strategy to make a series of mercaptobenzamide prodrugs represents a general new direction to make libraries that can be screened for anti-HIV activity.

Identification of novel 2-benzoxazolinone derivatives with specific inhibitory activity against the HIV-1 nucleocapsid protein

“…Over the years, different strategies have been proposed to achieve the effective inhibition of the biological functions of NC. Possible zinc-ejecting agents have been investigated for their ability to sequester the divalent cation, or interfere with metal coordination by the ZF residues [7,8]. However, a typically low specificity for retroviral versus mammalian ZF structures has thwarted further progress in this direction.…”

A 1:2 co-crystal of 2,2′-thiodibenzoic acid and triphenylphosphane oxide: crystal structure, Hirshfeld surface analysis and computational study

“…In medicine, is dianion is found in the salt Na[EtHg(SC 6 H 4 CO 2 )], which displays anti-fungal and anti-septic activities (Bigham & Copes, 2005). Other uses include as anti-corrosion agents (Chien et al, 2012), as reactive agents or modifiers for nanoparticles and electrochemical sensing (Cang et al, 2017;Sikarwar et al, 2014), as catalysts for organic syntheses (Yang et al, 2018;Selig & Miller, 2011) as well as being the precursor for some anti-viral and anti-microbial agents (Saha et al, 2017). The compound readily coordinates a wide variety of metals, in both neutral and anionic form, due to the presence of both hard (oxygen) and soft (sulfur) donor atoms and exhibits different modes of coordination.…”

Mercapto-Benzamide Inhibitors effects on HIV NCp7 Protein: a parameter-free DFT based structural study

“…As a result there are currently no NCp7 inhibitors that are used clinically to treat HIV infection. Some resarch groups are interested in the capacity of mercaptobenzamide(MB)-based molecules to IOP Publishing doi:10.1088/1757-899X/1265/1/012004 2 inhibit HIV-1 through the inactivation of NCp7 [12]. In this work we perform an AI structural minimization, based on DFT for the treatment of the electronic degrees of freedom, in order to study the action of the Mercapto-Benzamide (MB) class of molecules on the HIV Nucleocapsid [12] protein NCp7, a zinc finger protein [13].…”

“…Some resarch groups are interested in the capacity of mercaptobenzamide(MB)-based molecules to IOP Publishing doi:10.1088/1757-899X/1265/1/012004 2 inhibit HIV-1 through the inactivation of NCp7 [12]. In this work we perform an AI structural minimization, based on DFT for the treatment of the electronic degrees of freedom, in order to study the action of the Mercapto-Benzamide (MB) class of molecules on the HIV Nucleocapsid [12] protein NCp7, a zinc finger protein [13]. More specifically, stimulated by some studies on animal models, we were interested in the impact of the binding of these molecules to the structure of the C-terminal HIV NCp7 "zinc-knuckle" motif [14,15,16].…”

“…More specifically, stimulated by some studies on animal models, we were interested in the impact of the binding of these molecules to the structure of the C-terminal HIV NCp7 "zinc-knuckle" motif [14,15,16]. This motif binds and stabilizes the viral RNA and is thus essential for viral replication and maturation [12,17,18]. Due to its relevance for virus reproduction, the zinc-knuckle is little or nothing muted across HIV strands and undergoes relatively little mutation upon host infection.…”