Isosorbide-based peptidomimetics as inhibitors of hepatitis C virus serine protease. Issue 16 (15th August 2017)

• Record Type: Journal Article
• Authors: Portela, Aline C.; Barros, Thalita G.; Lima, Camilo H. da S.; Dias, Luiza R.S.; Azevedo, Pedro H.R. de A.; Dantas, Anna Sophia C.L.; Mohana-Borges, Ronaldo; Ventura, Gustavo T.; Pinheiro, Sergio; Muri, Estela M.F.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 16(2017)
• Page Start: 3661
• Page End: 3665
• Publication Date: 2017-08-15
• Subjects: Peptidomimetics -- Isosorbide -- HCV -- Serine proteases -- Molecular docking -- Molecular dynamic simulation -- MMPBSA; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.07.027
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Hepatitis C infection is a cause of chronic liver diseases such as cirrhosis and carcinoma. The current therapy for hepatitis C has limited efficacy and low tolerance. The HCV encodes a serine protease which is critical for viral replication, and few protease inhibitors are currently on the market. In this paper, we describe the synthesis and screening of novel isosorbide-based peptidomimetic inhibitors, in which the compounds 1d, 1e, and 1i showed significant inhibition of the protease activity in vitro at 100 µM. The compound 1e also showed dose-response (IC50 = 36 ± 3 µM) and inhibited the protease mutants D168A and V170A at 100 µM, indicating it as a promising inhibitor of the HCV NS3/4A protease. Our molecular modeling studies suggest that the activity of 1e is associated with a change in the interactions of S2 and S4 subsites, since that the increased flexibility favors a decrease in activity against D168A, whereas the appearance of a hydrophobic cavity in the S4 subsite increase the inhibition against V170A strain.