Cyclopeptides design as blockers against HCV p7 channel in silico. Issue 17 (22nd November 2019)

• Record Type: Journal Article
• Authors: Pang, Shichao; Zhao, Rongcheng; Wang, Shuqing; Wang, Jingfang
• Is Part Of: Molecular simulation. Volume 45:Issue 17(2019)
• Page Start: 1419
• Page End: 1425
• Publication Date: 2019-11-22
• Subjects: Hepatitis C virus -- p7 protein -- ion channel -- molecular dynamics -- cyclopeptides design; Molecular dynamics -- Computer simulation -- Periodicals; Statistical mechanics -- Computer simulation -- Periodicals; 539.6
• DOI: 10.1080/08927022.2019.1641604
• Languages: English
• ISSNs: 0892-7022

Abstract

ABSTRACT: The protein p7 in the hepatitis C virus (HCV) is a 63-residue transmembrane protein that oligomerizes to form an ion channel with cation selectivity. This protein is essential for the assembly and release of infectious viral particles. Structural analysis indicates that the bottleneck of the p7 hexamer channel is located on Asparagines at position 9 in the conical region with a pore radius of 3.9 Å, which is reduced to nearly 3.0 Å upon protonation. Amantadine and BIT225 binds in the hydrophobic pocket on the lipid-facing side of the p7 channel as allosteric inhibitors to stabilise the channel pore in a closed conformation. Here, we designed a series of cyclopeptides as inner channel blockers in the conical region based on chemical and physical characteristics of the channel bottleneck for the HCV p7 protein. As a result, cyclic-4-Asp is found to bind in the channel lumen between the gating residues Ile6 and Asn9 with a favourable binding affinity, perfectly fitting with the hydrophobic pocket in the conical region. Compared with amantadine and BIT225, we believe that the cylcopeptides have potential to be effective inhibitors against HCV p7 protein.