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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
A serine palmitoyltransferase inhibitor blocks hepatitis C virus replication in human hepatocytes
Gastroenterology, Volume 145, No. 4, Year 2013
Notification
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Description
Background & Aims Host cell lipid rafts form a scaffold required for replication of hepatitis C virus (HCV). Serine palmitoyltransferases (SPTs) produce sphingolipids, which are essential components of the lipid rafts that associate with HCV nonstructural proteins. Prevention of the de novo synthesis of sphingolipids by an SPT inhibitor disrupts the HCV replication complex and thereby inhibits HCV replication. We investigated the ability of the SPT inhibitor NA808 to prevent HCV replication in cells and mice. Methods We tested the ability of NA808 to inhibit SPT's enzymatic activity in FLR3-1 replicon cells. We used a replicon system to select for HCV variants that became resistant to NA808 at concentrations 4- to 6-fold the 50% inhibitory concentration, after 14 rounds of cell passage. We assessed the ability of NA808 or telaprevir to inhibit replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in mice with humanized livers (transplanted with human hepatocytes). NA808 was injected intravenously, with or without pegylated interferon alfa-2a and HCV polymerase and/or protease inhibitors. Results NA808 prevented HCV replication via noncompetitive inhibition of SPT; no resistance mutations developed. NA808 prevented replication of all HCV genotypes tested in mice with humanized livers. Intravenous NA808 significantly reduced viral load in the mice and had synergistic effects with pegylated interferon alfa-2a and HCV polymerase and protease inhibitors. Conclusions The SPT inhibitor NA808 prevents replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in cultured hepatocytes and in mice with humanized livers. It might be developed for treatment of HCV infection or used in combination with pegylated interferon alfa-2a or HCV polymerase or protease inhibitors. © 2013 by the AGA Institute.
Authors & Co-Authors
Katsume, Asao
Japan, Tokyo
Tokyo Metropolitan Institute of Medical Science
Japan, Chuo-ku
Chugai Pharmaceutical Co., Ltd.
Tokunaga, Yuko
Japan, Tokyo
Tokyo Metropolitan Institute of Medical Science
Hirata, Yuichi
Japan, Tokyo
Tokyo Metropolitan Institute of Medical Science
Munakata, Tsubasa
Japan, Tokyo
Tokyo Metropolitan Institute of Medical Science
Saito, Makoto
Japan, Tokyo
Tokyo Metropolitan Institute of Medical Science
Hayashi, Hitohisa
Japan, Tokyo
Tokyo Metropolitan Institute of Medical Science
Okamoto, Koichi
Japan, Chuo-ku
Chugai Pharmaceutical Co., Ltd.
Ohmori, Yusuke
Japan, Chuo-ku
Chugai Pharmaceutical Co., Ltd.
Kusanagi, Isamu
Japan, Gotemba
Chugai Research Institute for Medical Science, Inc
Fujiwara, Shinya
Japan, Chuo-ku
Chugai Pharmaceutical Co., Ltd.
Tsukuda, Takuo
Japan, Chuo-ku
Chugai Pharmaceutical Co., Ltd.
Aoki, Yuko
Japan, Chuo-ku
Chugai Pharmaceutical Co., Ltd.
Klumpp, Klaus
United States, Nutley
Hoffmann-la Roche Inc.
Tsukiyama-Kohara, Kyoko
Japan, Kagoshima
Kagoshima University
El-Gohary, Ahmed M.
Egypt, Ismailia
Faculty of Medicine
Sudoh, Masayuki
Japan, Chuo-ku
Chugai Pharmaceutical Co., Ltd.
Kohara, Michinori
Japan, Tokyo
Tokyo Metropolitan Institute of Medical Science
Statistics
Citations: 33
Authors: 17
Affiliations: 6
Identifiers
Doi:
10.1053/j.gastro.2013.06.012
ISSN:
00165085
e-ISSN:
15280012
Research Areas
Infectious Diseases