Probing Mercaptobenzamides as HIV Inactivators via Nucleocapsid Protein 7. (25th April 2017)

• Record Type: Journal Article
• Authors: Saha, Mrinmoy; Scerba, Michael T.; Shank, Nathaniel I.; Hartman, Tracy L.; Buchholz, Caitlin A.; Buckheit, Robert W.; Durell, Stewart R.; Appella, Daniel H.
• Is Part Of: ChemMedChem. Volume 12:Number 10(2017)
• Page Start: 714
• Page End: 721
• Publication Date: 2017-04-25
• Subjects: antiviral agents -- HIV -- mercaptobenzamides -- nucleocapsid protein 7 -- prodrugs; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700141
• Languages: English
• ISSNs: 1860-7179

Abstract

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 is an attractive target for drug development. However, the development of drug‐like molecules that inhibit NCp7 has been a significant challenge. In this study, a series of novel 2‐mercaptobenzamide prodrugs were investigated for anti‐HIV activity in the context of NCp7 inactivation. The molecules were 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 side chain. 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. Abstract : The bare‐knuckle round in the fight against HIV: Mercapotobenzamide derivatives could become the next generation of drugs to treat HIV infection by targeting and inactivating nucleocapsid protein 7 (NCp7). This protein contains two zinc‐coordinated knuckles that bind to HIV RNA and are essential for viral replication. Certain mercaptobenzamide derivatives promote the acetylation of NCp7, loss of zinc coordination, and eliminate the ability of NCp7 to bind HIV RNA. Herein we describe how to quickly make mercaptobenzamide analogues to screen for antiviral activity.