Host sphingolipid biosynthesis as a target for hepatitis C virus therapy.
An estimated 170 million individuals worldwide are infected with hepatitis C virus (HCV), a serious cause of chronic liver disease. Current interferon-based therapy for treating HCV infection has an unsatisfactory cure rate, and the development of more efficient drugs is needed. During the early stages of HCV infections, various host genes are differentially regulated, and it is possible that inhibition of host proteins affords a therapeutic strategy for treatment of HCV infection. Using an HCV subgenomic replicon cell culture system, here we have identified, from a secondary fungal metabolite, a lipophilic long-chain base compound, NA255 (1), a previously unknown small-molecule HCV replication inhibitor. NA255 prevents the de novo synthesis of sphingolipids, major lipid raft components, thereby inhibiting serine palmitoyltransferase, and it disrupts the association among HCV nonstructural (NS) viral proteins on the lipid rafts. Furthermore, we found that NS5B protein has a sphingolipid-binding motif in its molecular structure and that the domain was able to directly interact with sphingomyelin. Thus, NA255 is a new anti-HCV replication inhibitor that targets host lipid rafts, suggesting that inhibition of sphingolipid metabolism may provide a new therapeutic strategy for treatment of HCV infection.
Sakamoto
Hiroshi
H
Kamakura Research Laboratories, Chugai Pharmaceutical Co. Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. sakamotohrs@chugai-pharm.co.jp
Okamoto
Koichi
K
Aoki
Masahiro
M
Kato
Hideyuki
H
Katsume
Asao
A
Ohta
Atsunori
A
Tsukuda
Takuo
T
Shimma
Nobuo
N
Aoki
Yuko
Y
Arisawa
Mikio
M
Kohara
Michinori
M
Sudoh
Masayuki
M
D002460:Cell Line; D002951:Citrates / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D010666:Phenylpropionates / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D013107:Sphingolipids / Q000096:biosynthesis*; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014779:Virus Replication
D002951:Citrates; C507637:NA 255; D010666:Phenylpropionates; D013107:Sphingolipids; D017361:Viral Nonstructural Proteins