Soraphen A: A Probe for Investigating the Role of de Novo Lipogenesis during Viral Infection.
Many viruses including the hepatitis C virus (HCV) induce changes to the infected host cell metabolism that include the up-regulation of lipogenesis to create a favorable environment for the virus to propagate. The enzyme acetyl-CoA carboxylase (ACC) polymerizes to form a supramolecular complex that catalyzes the rate-limiting step of de novo lipogenesis. The small molecule natural product Soraphen A (SorA) acts as a nanomolar inhibitor of acetyl-CoA carboxylase activity through disruption of the formation of long highly active ACC polymers from less active ACC dimers. We have shown that SorA inhibits HCV replication in HCV cell culture models expressing subgenomic and full-length replicons (IC50 = 5 nM) as well as a cell culture adapted virus. Using coherent anti-Stokes Raman scattering (CARS) microscopy, we have shown that SorA lowers the total cellular lipid volume in hepatoma cells, consistent with a reduction in de novo lipogenesis. Furthermore, SorA treatment was found to depolymerize the ACC complexes into less active dimers. Taken together, our results suggest that SorA treatment reverses HCV-induced lipid accumulation and demonstrate that SorA is a valuable probe to study the roles of ACC polymerization and enzymatic activity in viral pathogenesis.
Life Sciences Division, National Research Council of Canada , Ottawa, Ontario, Canada K1A 0R6.
Ragunath
R
Singaravelu
Life Sciences Division, National Research Council of Canada , Ottawa, Ontario, Canada K1A 0R6.
Geneviève F
GF
Desrochers
Life Sciences Division, National Research Council of Canada , Ottawa, Ontario, Canada K1A 0R6.
Prashanth
P
Srinivasan
Life Sciences Division, National Research Council of Canada , Ottawa, Ontario, Canada K1A 0R6.
Shifawn
S
O'Hara
Life Sciences Division, National Research Council of Canada , Ottawa, Ontario, Canada K1A 0R6.
Rodney K
RK
Lyn
Institute of Pharmaceutical Biotechnology, Saarland University , P.O. Box 151150, D-66041 Saarbrücken, Germany.
Rolf
R
Müller
Immunology and Infectious Diseases, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Newfoundland, Canada A1B 3V6.
Daniel M
DM
Jones
Immunology and Infectious Diseases, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Newfoundland, Canada A1B 3V6.
Rodney S
RS
Russell
Life Sciences Division, National Research Council of Canada , Ottawa, Ontario, Canada K1A 0R6.
John Paul
JP
Pezacki
CARS; HCV; coherent anti-Stokes Raman spectroscopy; hepatitis C virus; lipids