title: Macrocyclic Hepatitis C Virus NS3/4A Protease Inhibitors: An Overview of Medicinal Chemistry.
abstract: Hepatitis C virus (HCV) is a causative agent of hepatitis C infectious disease that primarily affects the liver, ranging in severity from a mild illness lasting a few weeks to a lifelong illness. The 9.6 kb RNA genome of HCV encodes approximately 3000 amino acid polyprotein that must be processed by host and viral proteases into both structural (S) and non-structural (NS) proteins, respectively. Targeting the serine protease NS3 with an activating factor NS4A, i.e., NS3/4A has been considered as one of the most attractive targets for the development of anti-HCV therapy. Although there is no vaccine available, antiviral medicines cure approximately 90% of the persons with hepatitis C infection. On the other hand, efficacy of these medications can be hampered due to the rapid drug and cross resistances. To date, all developed HCV NS3/4A inhibitors are mainly peptide-based compounds derived from the cleavage products of substrate. Specifically macrocyclic peptidomimetics have rapidly emerged as a classical NS3/4A protease inhibitors for treating the HCV infection. This review highlights the development of macrocyclic anti-HCV NS3/4A protease, as well as clinically important inhibitors developed from linear peptides, discovered during the last 12 years (2003-2015) from all sources, including laboratory synthetic methods, virtual screening and structure-based molecular docking studies. We emphasize the rationale behind the design, study of structure-activity relationships, and mechanism of inhibitions and cellular effect of the macrocyclic inhibitors.
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, D-53121 Bonn, Germany. thanigai@uni-bonn.de.
authors.forename: Thanigaimalai
authors.initials: T
authors.lastname: Pillaiyar
authors.forename: Vigneshwaran
authors.initials: V
authors.lastname: Namasivayam
authors.forename: Manoj
authors.initials: M
authors.lastname: Manickam
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D057786:Peptidomimetics / Q000737:chemistry / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds; D057786:Peptidomimetics; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus