Discovery and development of NS5A inhibitors

The HCV genome. NS5A in the bottom row, second from the right.

Nonstructural protein 5A (NS5A) inhibitors are direct acting antiviral agents (DAAs) that target viral proteins, and their development was a culmination of increased understanding of the viral life cycle combined with advances in drug discovery technology.[1][2] However, their mechanism of action is complex and not fully understood.[2] NS5A inhibitors were the focus of much attention when they emerged as a part of the first curative treatment for hepatitis C virus (HCV) infections in 2014.[3] Favorable characteristics have been introduced through varied structural changes, and structural similarities between NS5A inhibitors that are clinically approved are readily apparent.[4][5] Despite the recent introduction of numerous new antiviral drugs, resistance is still a concern and these inhibitors are therefore always used in combination with other drugs.[6][7]

  1. ^ Gogela, Neliswa A.; Lin, Ming V.; Wisocky, Jessica L.; Chung, Raymond T. (12 March 2015). "Enhancing Our Understanding of Current Therapies for Hepatitis C Virus (HCV)". Current HIV/AIDS Reports. 12 (1): 68–78. doi:10.1007/s11904-014-0243-7. PMC 4373591. PMID 25761432.
  2. ^ a b Pawlotsky, Jean-Michel (August 2013). "NS5A inhibitors in the treatment of hepatitis C". Journal of Hepatology. 59 (2): 375–382. doi:10.1016/j.jhep.2013.03.030. PMID 23567084.
  3. ^ Do, Albert; Mittal, Yash; Liapakis, AnnMarie; Cohen, Elizabeth; Chau, Hong; Bertuccio, Claudia; Sapir, Dana; Wright, Jessica; Eggers, Carol; Drozd, Kristine; Ciarleglio, Maria; Deng, Yanhong; Lim, Joseph K.; Jhaveri, Ravi (27 August 2015). "Drug Authorization for Sofosbuvir/Ledipasvir (Harvoni) for Chronic HCV Infection in a Real-World Cohort: A New Barrier in the HCV Care Cascade". PLOS ONE. 10 (8): e0135645. Bibcode:2015PLoSO..1035645D. doi:10.1371/journal.pone.0135645. PMC 4552165. PMID 26312999.
  4. ^ Tong, Ling; Yu, Wensheng; Coburn, Craig A.; Meinke, Peter T.; Nair, Anilkumar G.; Dwyer, Michael P.; Chen, Lei; Selyutin, Oleg; Rosenblum, Stuart B.; Jiang, Yueheng; Fells, James; Hu, Bin; Zhong, Bin; Soll, Richard M.; Liu, Rong; Agrawal, Sony; Xia, Ellen; Zhai, Ying; Kong, Rong; Ingravallo, Paul; Nomeir, Amin; Asante-Appiah, Ernest; Kozlowski, Joseph A. (July 2016). "Alternative core development around the tetracyclic indole class of HCV NS5A inhibitors". Bioorganic & Medicinal Chemistry Letters. 26 (20): 5132–5137. doi:10.1016/j.bmcl.2016.07.057. PMID 27634194.
  5. ^ Lemm, J. A.; Leet, J. E.; O'Boyle, D. R.; Romine, J. L.; Huang, X. S.; Schroeder, D. R.; Alberts, J.; Cantone, J. L.; Sun, J.-H.; Nower, P. T.; Martin, S. W.; Serrano-Wu, M. H.; Meanwell, N. A.; Snyder, L. B.; Gao, M. (16 May 2011). "Discovery of Potent Hepatitis C Virus NS5A Inhibitors with Dimeric Structures". Antimicrobial Agents and Chemotherapy. 55 (8): 3795–3802. doi:10.1128/AAC.00146-11. PMC 3147613. PMID 21576451.
  6. ^ Fridell, R. A.; Qiu, D.; Wang, C.; Valera, L.; Gao, M. (28 June 2010). "Resistance Analysis of the Hepatitis C Virus NS5A Inhibitor BMS-790052 in an In Vitro Replicon System". Antimicrobial Agents and Chemotherapy. 54 (9): 3641–3650. doi:10.1128/AAC.00556-10. PMC 2935007. PMID 20585111.
  7. ^ Asselah, Tarik; Boyer, Nathalie; Saadoun, David; Martinot-Peignoux, Michele; Marcellin, Patrick (January 2016). "Direct-acting antivirals for the treatment of hepatitis C virus infection: optimizing current IFN-free treatment and future perspectives". Liver International. 36: 47–57. doi:10.1111/liv.13027. PMID 26725897.