Helmholtz Institut für Pharmazeutische Forschung Saarland, Helmholtz Zentrum für Infektionsforschung and Universität des Saarlandes, 66123 Saarbrücken (Germany).
Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).
Angew Chem Int Ed Engl. 2015 Dec 14;54(51):15560-4. doi: 10.1002/anie.201508277. Epub 2015 Oct 30.
The bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half-life in mice and antitumor efficacy in a melanoma mouse model.
苯并酰胺是从海绵中提取的天然产物，已被鉴定为蛋氨酸氨肽酶（MetAPs）的抑制剂，它们被广泛研究作为抗癌化合物。我们开始了一项多学科的项目，通过发酵陆地粘细菌 M. virescens 来供应苯并酰胺，阐明它们的生物合成，并优化它们作为药物先导的特性。生物合成途径的特征表明，细菌对苯并酰胺的抗性是由粘细菌 MetAP 蛋白的 Leu154 赋予的，这使得整个基因簇能够转移到更适合生产的宿主 M. xanthus DK1622 中。微生物衍生的苯并酰胺的半合成和全合成的组合产生了一个优化的衍生物，该衍生物在纳摩尔范围内具有高细胞效力和高代谢稳定性，这转化为在小鼠中的半衰期延长和在黑色素瘤小鼠模型中的抗肿瘤疗效提高。
