In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus.
Hepatitis delta virus (HDV) can dramatically worsen liver disease in patients coinfected with hepatitis B virus (HBV). No effective medical therapy exists for HDV. The HDV envelope requires HBV surface antigen proteins provided by HBV. Once inside a cell, however, HDV can replicate its genome in the absence of any HBV gene products. In vitro, HDV virion assembly is critically dependent on prenyl lipid modification, or prenylation, of its nucleocapsid-like protein large delta antigen. To overcome limitations of current animal models and to test the hypothesis that pharmacologic prenylation inhibition can prevent the production of HDV virions in vivo, we established a convenient mouse-based model of HDV infection capable of yielding viremia. Such mice were then treated with the prenylation inhibitors FTI-277 and FTI-2153. Both agents were highly effective at clearing HDV viremia. As expected, HDV inhibition exhibited duration-of-treatment dependence. These results provide the first preclinical data supporting the in vivo efficacy of prenylation inhibition as a novel antiviral therapy with potential application to HDV and a wide variety of other viruses.
Bordier
Bruno B
BB
Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California 94305, USA.
Ohkanda
Junko
J
Liu
Ping
P
Lee
So-Young
SY
Salazar
F H
FH
Marion
Patricia L
PL
Ohashi
Kazuo
K
Meuse
Leonard
L
Kay
Mark A
MA
Casey
John L
JL
Sebti
Said M
SM
Hamilton
Andrew D
AD
Glenn
Jeffrey S
JS
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051231:Farnesyltranstransferase; D006509:Hepatitis B / Q000150:complications; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D003699:Hepatitis D / Q000150:complications / Q000188:drug therapy / Q000821:virology; D003698:Hepatitis Delta Virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects*; D017393:RNA Editing; D014766:Viremia / Q000188:drug therapy; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C096856:FTI 277; D006514:Hepatitis B Surface Antigens; D009842:Oligopeptides; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase