深在性真菌症治療薬ミカファンギン(FK463)の工業化研究

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In 1989, in the course of our screening for new antifungal antibiotics with cell wall synthesis inhibition activity, FR901379 (WF11899A) was discovered in the culture broth of Coleophoma empetri F-11899. The strain was isolated from a soil sample collected in Iwaki city, Fukushima-prefecture, Japan. Because FR901379 had hemolytic activity, we decided to screen for semi-synthesis derivatives with low toxicity and high antifungal activity and evaluated many derivatives with substituted side chains. We started by using Actinoplanes utahensis to replace the palmitoyl group of FR901379 with other organic acids. After synthesizing several hundred organic acids and making repeated derivatives, we discovered FR131535, which had similar antifungal activity to FR901379 in vitro and in vivo and low hemolytic activity. It was not however selected as a development candidate because of insufficient antifungal activity. In the search for a more potent compound, we hypothesized that a compound with a similar molecular structure to FR131535 might produce a good antifungal drug. We therefore began the screening of Fujisawa's original acylase using a specially devised and effective screening system. After discovering "FR901379 Acylase" produced by Streptomyces sp. No. 6907, we continued with our evaluation of derivatives. We finally selected FK463 as a candidate compound for commercial drug development. In 1990, to establish an industrial manufacturing method for Micafungin (FK463), our laboratories (Fermentation Development Laboratories) commenced the following development research : (1) strain improvement of Coleophoma, (2) screening of "FR901379 Acylase"-producing strains, (3) studies to increase the scale of fermentation of FR901379 and "FR901379 Acylase", (4) determination of effective purification procedures for FR901379, a key intermediate of FR179642 and FK463, and (5) development of a HPLC assay system to measure the amount of objective compounds and impurities. Micafungin (general name, Trade mark : Funguard, Development No. : FK463) was launched in Japan on December 6, 2002. Approval in the USA and EU is pending and expected shortly.
社団法人日本生物工学会の論文
2005-03-25

深在性真菌症治療薬ミカファンギン(FK463)の工業化研究

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