Inhibition of the interaction between NS3 protease and HCV IRES with a small peptide: a novel therapeutic strategy.
Recently, we have demonstrated that the protease domain of NS3 alone can bind specifically to hepatitis C virus (HCV) internal ribosome entry site (IRES) near the initiator AUG, dislodges human La protein and inhibits translation in favor of viral RNA replication. Here, by using a computational approach, the contact points of the protease on the HCV IRES were putatively mapped. A 30-mer NS3 peptide was designed from the predicted RNA-binding region that retained RNA-binding ability and also inhibited IRES-mediated translation. This peptide was truncated to 15 mer and this also demonstrated ability to inhibit HCV RNA-directed translation as well as replication. More importantly, its activity was tested in an in vivo mouse model by encapsulating the peptide in Sendai virus virosomes followed by intravenous delivery. The study demonstrates for the first time that the HCV NS3-IRES RNA interaction can be selectively inhibited using a small peptide and reports a strategy to deliver the peptide into the liver.
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
Upasana
U
Ray
Chaitrali L
CL
Roy
Anuj
A
Kumar
Prashant
P
Mani
Agnel P
AP
Joseph
G
G
Sudha
Debi P
DP
Sarkar
N
N
Srinivasan
Saumitra
S
Das
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D014176:Protein Biosynthesis; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012270:Ribosomes / Q000187:drug effects* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D010455:Peptides; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases