Discovery and development of NS5A inhibitors

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.
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