Hepatitis C virus nonstructural protein 5A

Structure

NS5A is derived from a large polyprotein that is translated from the HCV genome, and undergoes post-translation processing by nonstructural protein 3 (NS3) viral protease.{{cite book | access-date = 8 January 2021

NS5A has three structurally different domains: Domain I was demonstrated to be an alternative dimeric structure by crystallography, while domain II and III remained unfolded. Furthermore, the conformational flexibility of NS5A plays an important role in multiple HCV infection stages. It is also possible that NS5A is a critical component during HCV replication and subcellular localization, which may shed light on the poorly understood HCV life cycle. Additionally, NS5A has been shown to modulate the polymerase activity of NS5B, an RNA-dependent RNA polymerase (RdRp). Intriguingly, NS5A may be a RNA binding protein because it is able to bind to the 3’UTR of the plus and minus HCV RNA strands. Moreover, NS5A is a key mediator in regulating host cell function and activity upon HCV infection. Therefore, NS5A has been extensively studied in HCV research also due to its capability to regulate the interferon (IFN) response of the host cells. Because NS5A exerts functionally essential effects in regulation of viral replication, assembly and egress, it has been considered a potential drug target for antiviral therapeutic intervention. Indeed, small molecule drugs efficiently targeting NS5A displayed a much higher potency in controlling HCV infection than other drugs. Therefore, NS5A related researches would have important implications in single molecule drug design and pegIFN-free direct-acting antiviral (DAA) combination therapies.

As a drug target

Many antiviral drugs target NS5A, e.g. to treat hepatitis C; they are often described as NS5A inhibitors, and they are often used in combination with NS5B inhibitors:

• FDA-approved:
  • Ledipasvir, approved on October 10, 2014 in a fixed-dose combination (FDC) with sofosbuvir
  • Ombitasvir, approved on December 19, 2014 in a FDC with paritaprevir and ritonavir, co-packaged with dasabuvir
  • Daclatasvir, approved on July 24, 2015
  • Elbasvir, approved on January 28, 2016 in a FDC with grazoprevir
  • Velpatasvir, approved on June 28, 2016 in a FDC with sofosbuvir and on July 17, 2017 in a FDC with sofosbuvir and voxilaprevir
  • Pibrentasvir, approved on August 3, 2017 in a FDC with glecaprevir
• Investigational drugs:
  • Odalasvir
  • Ravidasvir
  • Ruzasvir
  • Samatasvir

References

References

1. (2016-02-19). "Phosphoproteomics Identified an NS5A Phosphorylation Site Involved in Hepatitis C Virus Replication". The Journal of Biological Chemistry.
2. (2017-07-15). "Serine 235 Is the Primary NS5A Hyperphosphorylation Site Responsible for Hepatitis C Virus Replication". Journal of Virology.
3. (2018-10-15). "Sequential S232/S235/S238 Phosphorylation of the Hepatitis C Virus Nonstructural Protein 5A". Journal of Virology.
4. (2019-12-01). "Serine 229 Balances the Hepatitis C Virus Nonstructural Protein NS5A between Hypo- and Hyperphosphorylated States". Journal of Virology.
5. (2020-09-15). "Sequential Phosphorylation of the Hepatitis C Virus NS5A Protein Depends on NS3-Mediated Autocleavage between NS3 and NS4A". Journal of Virology.