Structure-Based Discovery of Triphenylmethane Derivatives as Inhibitors of Hepatitis C Virus Helicase

Abstract

Hepatitis C virus nonstructural protein 3 (HCV NS3) helicase is believed to be essential for viral replication and has become an attractive target for the development of antiviral drugs. A fluorescence resonant energy transfer helicase assay was established for fast screening of putative inhibitors selected from virtual screening using the program DOCK. Soluble blue HT (1) was first identified as a novel HCV helicase inhibitor. Crystal structure of the NS3 helicase in complex with soluble blue HT shows that the inhibitor bears a significantly higher binding affinity mainly through a 4-sulfonatophenylaminophenyl group, and this is consistent with the activity assay. Subsequently, fragment-based searches were utilized to identify triphenylmethane derivatives for more potent inhibitors. Lead optimization resulted in a 3-bromo-4-hydroxyl substituted derivative 12 with an EC(50) value of 2.72 microM to Ava.5/Huh-7 cells and a lower cytotoxicity to parental Huh-7 cells (CC(50) = 10.5 microM), and it indeed suppressed HCV replication in the HCV replicon cells. Therefore, these inhibitors with structural novelty may serve as a useful scaffold for the discovery of new HCV NS3 helicase inhibitors.

RNA helicases in infection and disease

“…Other in vitro-inhibitor series of HCV-NS3 helicase activity include benzimidazoles, 224 acyl sulfonamides, 225 tropolones, 226 acridons 227 and triphenylmethanes. 228 HCV is responsible for more than 50% of all liver cancers, and anti-HCV drugs are therefore effective against both viral infection and cancer. Antiviral and anti-cancer therapies targeting RIG-like receptors?…”

Unique Helicase Determinants in the Essential Conjugative TraI Factor from Salmonella enterica Serovar Typhimurium Plasmid pCU1

“…Alternatively, equation 2 could be used to yield a value for K D as previously described (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)53):…”

“…As a result, helicases are key players in a wide variety of DNA and RNA metabolic processes, such as recombination, chromatin remodeling, and DNA transport (4)(5)(6). Most recently, helicases have emerged as potential therapeutic targets for diseases ranging from cancer to Gram-positive bacterial infections (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Classified into six superfamilies, superfamily 1 and 2 (SF1 and SF2) helicases are the most similar, sharing up to seven conserved sequence motifs and core RecA-like folds (1)(2)(3).…”

X-ray structure and conformational study of tris(2-(dimethylamino)phenyl)methanol salt derivatives: Roles of anions and hydrogen bond

“…The molecule of the tetrachlorocobaltate salt possesses approximately C3 symmetry. The cation part structure of molecules ([(2-Me 2 N þ HeC 6 H 4 ) 3 CeO À ] 2þ , [LH 2 ] 2þ ) was maintained by three zwitterionic H-bonds [26,27], which share a same central oxygen anion. The three benzene rings of the [LH 2 ] 2þ cation adopt a Å)) and the þ NeH/O À angles (140.78e140.80 ) are almost equivalent.…”