ABSTRACT
In recent years, nonstructural protein 5A (NS5A) has rapidly emerged as a promising therapeutic target for Hepatitis C (HCV) virus therapy. It is involved in both viral RNA replication and virus assembly and NS5A plays a critical role in the regulation of HCV life cycle. NS5A replication complex inhibitors (NS5A RCIs) have demonstrated strong antiviral activity in vitro and in vivo. However, wild-type resistance mutations and a wide range of genotypes significantly reduce their clinical efficacy. The exact mechanism of NS5A action still remains elusive, therefore several in silico models have been constructed to gain insight into the drug binding and subsequent structural optimization to overcome resistance. This paper provides a comprehensive overview of the computational studies towards NS5A mechanism of action and the design of novel small-molecule inhibitors.
Subject(s)
Antiviral Agents/pharmacology , Computer Simulation , Drug Design , Hepacivirus/drug effects , Small Molecule Libraries/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Conformation , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Virus Replication/drug effectsABSTRACT
Non-structural 5A (NS5A) protein plays a crucial role in the replication of hepatitis C virus (HCV) and during the past decade has attracted increasing attention as a promising biological target for the treatment of viral infections and related disorders. Small-molecule NS5A inhibitors have shown significant antiviral activity in vitro and in vivo. Several lead molecules are reasonably regarded as novel highly potent drug candidates with favorable ADME features and tolerable side effects. The first-in-class daclatasvir has recently been launched into the market and 14 novel molecules are currently under evaluation in clinical trials. From this perspective, we provide an overview of the available chemical space of small-molecule NS5A inhibitors and their PK properties, mainly focusing on the diversity in structure and scaffold representation.