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These results suggest that FR901277 inhibits the elastase activity potently both in vitro and in vivo, and that elastase may play a role at least in part in pathogenesis of pulmonary emphysema.

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A novel human leukocyte elastase inhibitor, FR901277 was discovered in the fermentation broth of Streptomyces resistomycificus No. 7622. FR901277 has a molecular weight of 961 and a molecular formula of C47H63N9O13.The mode of inhibition is competitive, with a Ki of 1.2 x 10"8m. Oral administration of FR901277 at doses from 32 to 320 mg/kg significantly prevented human leukocyte elastase-induced foot edema in mice.Humanleukocyte elastase (HLE) is considered to be the most destructive enzyme present in the body.The enzyme hydrolyzes several connective tissue components such as elastin, proteoglycan and certain types of collagen. It is released from polymorphonuclear leukocytes by inflammatory stimuli and may play a role in destructive processes associated with chronic inflammatory diseases such as emphysema2). Therefore, inhibitors of HLEmay have value in medicine.In our search for microbially produced HLEinhibitors, we discovered FR901277. In this report, we address the identification and fermentation of the producing microorganism, as well as the isolation, physico-chemical and biological properties of the inhibitor. TaxonomicCharacterizationThe methods and media described by Shirling and Gottlieb3*, and Waksman4) were employed for the taxonomic study. The preparation of cells and the determination of the isomer of diaminopimelic acid were performed by the procedures of Becker et al.5\Fermentation A seed medium (200ml) containing soluble starch 1%, sucrose 1%, glucose 1%, cotton seed meal 1%, Polypepton 0.5%, soybean meal 0.5% and CaCO30.1% prepared in tap-water was added to each of twelve 500-ml Erlenmyer flasks and was sterilized at 120°C for 30 minutes. A loopful of Streptomyces FR901277 is identical to WS7622A1).

Intratracheal (i.t.) or intravenous (i.v.) administration of FR90145 1, a potent inhibitor of human leukocyte elastase (HLE) prevented HLE-induced lung hemorrhage in hamsters with ED50 values of 10.5 /ig/site and 8. 1 mg/kg, respectively. al-Antitrypsin (al-AT) also showed inhibitory effect in this model. However, the ED50 value by i.t. injection of FR901451was 20-fold lower than that of al-AT. Moreover, FR901451 i.t. significantly modulated porcine pancreas elastase (PPE)-induced changes of the respiratory mechanics in hamsters. The ED50 values were 529 /zg/site and 244 //g/site, which were expressed by static lung compliance (Cst) and vital capacity (VC) of the lungs, respectively.These results suggest that FR90145 1 could be clinically useful agent for the treatment of the destructive lung disease such as pulmonary emphysema.