Identification of a class of HCV inhibitors directed against the nonstructural protein NS4B.
New classes of drugs are needed to combat hepatitis C virus (HCV), an important worldwide cause of liver disease. We describe an activity of a key domain, an amphipathic helix we termed 4BAH2, within a specific HCV nonstructural protein, NS4B. In addition to its proposed role in viral replication, we validate 4BAH2 as essential for HCV genome replication and identify first-generation small-molecule inhibitors of 4BAH2 that specifically prevent HCV replication within cells. Mechanistic studies reveal that the inhibitors target 4BAH2 function by preventing either 4BAH2 oligomerization or 4BAH2 membrane association. 4BAH2 inhibitors represent an additional class of compounds with potential to effectively treat HCV.
Cho
Nam-Joon
NJ
Division of Gastroenterology and Hepatology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
Dvory-Sobol
Hadas
H
Lee
Choongho
C
Cho
Sang-Joon
SJ
Bryson
Paul
P
Masek
Marilyn
M
Elazar
Menashe
M
Frank
Curtis W
CW
Glenn
Jeffrey S
JS
D000596:Amino Acids / Q000378:metabolism; D000998:Antiviral Agents / Q000032:analysis* / Q000145:classification / Q000494:pharmacology*; D002460:Cell Line; D016679:Genome, Viral / Q000235:genetics; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology / Q000648:ultrastructure; D006801:Humans; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D053835:Unilamellar Liposomes / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000648:ultrastructure; D014779:Virus Replication / Q000187:drug effects
D000596:Amino Acids; D000998:Antiviral Agents; C080107:NS4B protein, flavivirus; D053835:Unilamellar Liposomes; D017361:Viral Nonstructural Proteins