Monday, July 27, 2009
P96
NA255: Anti-hepatitis C virus agent produced by Fusarium incarnatum and fermentation of NA808, a derivative of NA255
Yoshie Nagahashi1, Tatusya Ito1, Miyako Masubuchi1, Yuuichi Yamaguchi1, Hiroshi Sakamoto2, Masayuki Sudoh2, Kenichi Kawasaki3, Takuo Tsukuda3, Hideyuki Katoh1, Toru Okuda4, and Masahiro Aoki1. (1) Pharmaceutical technology department, Chugai pharmaceutical Co.,LTD., 200 Kajiwara Kamakura, Kanagawa, 247-8530, Japan, (2) Pharmaceutical research department 2, Chugai pharmaceutical Co.,LTD., 200 Kajiwara Kamakura, Kanagawa, 247-8530, Japan, (3) Chemistry research department 2, Chugai pharmaceutical Co.,LTD., 200 Kajiwara Kamakura, Kanagawa, 247-8530, Japan, (4) Mycology & Metabolic Diversity Research Center, Tamagawa University, 6-1-1 Tamagawa gakuen Machida, Tokyo, 194-8610, Japan
Infection with hepatitis C virus (HCV) is one of the serious causes of chronic liver disease. To identify an HCV replication inhibitor as a lead compound of an anti-HCV agent, we carried out cell-based high throughput screening using an HCV subgenomic replicon cell culture system. As a result of the screening using our natural product libraries mainly consisting of actinomycetal and fungal metabolites, we identified NA255 a strong HCV replication inhibitor from secondary fungal metabolites of Fusarium incarnatum F1476 isolated from samples collected in Japan
NA255 has a unique chemical structure containing a long lipophilic side-chain, a polar head consisting of three carboxylic acids and a prenylated tyrosine moiety. The biosynthetic pathway of NA255 was studied based on feeding experiments with 13C labeled precursors . Biosynthetic pathway of NA255 will be proposed.
NA808 is a derivative of NA255 and it was selected as a clinical drug candidate for the treatment of HCV. The clinical study of NA808 is now ongoing. To develop the industrial production of NA808, we examined NA808 fermentation with unnatural amino acid feeding using mutant strains of Fusarium incarnatum F1476. Strain developments and improvement of the culture conditions improved the productivity of NA808 to 1200 mg/L in flask culture. A scale-up culture was also successful using a 200-L jar fermentor.
NA255 has a unique chemical structure containing a long lipophilic side-chain, a polar head consisting of three carboxylic acids and a prenylated tyrosine moiety. The biosynthetic pathway of NA255 was studied based on feeding experiments with 13C labeled precursors . Biosynthetic pathway of NA255 will be proposed.
NA808 is a derivative of NA255 and it was selected as a clinical drug candidate for the treatment of HCV. The clinical study of NA808 is now ongoing. To develop the industrial production of NA808, we examined NA808 fermentation with unnatural amino acid feeding using mutant strains of Fusarium incarnatum F1476. Strain developments and improvement of the culture conditions improved the productivity of NA808 to 1200 mg/L in flask culture. A scale-up culture was also successful using a 200-L jar fermentor.
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