Center for Natural Products Research, Faculty of Chemistry, University of Havana, Zapata y G, 10400, La Habana (Cuba).
ChemMedChem. 2014 Oct;9(10):2351-9. doi: 10.1002/cmdc.201402140. Epub 2014 Jul 2.
The development of selective inhibitors of microbial metallo-aminopeptidases is an important goal in the pursuit of antimicrobials for therapeutic applications. Herein, we disclose a combinatorial approach relying on two Ugi reactions for the generation of peptidomimetics inspired by natural metallo-aminopeptidase inhibitors. The library was screened for inhibitory activity against the neutral metallo-aminopeptidase of Escherichia coli (ePepN) and the porcine kidney cortex metallo-aminopeptidase (pAPN), which was used as a model of the M1-aminopeptidases of mammals. Six compounds showed typical dose-response inhibition profiles toward recombinant ePepN, with two of them being very potent and highly selective for ePepN over pAPN. Another compound showed moderate ePepN inhibition but total selectivity for this bacterial enzyme over its mammalian orthologue at concentrations of physiological relevance. This strategy proved to be useful for the identification of lead compounds for further optimization and development.
开发微生物金属氨基肽酶的选择性抑制剂是寻求治疗应用抗菌药物的一个重要目标。在此，我们披露了一种组合方法，该方法依赖于两种 Ugi 反应来产生受天然金属氨基肽酶抑制剂启发的肽模拟物。该文库针对大肠杆菌（ePepN）的中性金属氨基肽酶和猪肾皮质金属氨基肽酶（pAPN）进行了抑制活性筛选，后者被用作哺乳动物 M1-氨基肽酶的模型。六种化合物对重组 ePepN 表现出典型的剂量反应抑制谱，其中两种对 ePepN 具有很强的抑制作用，对 pAPN 具有高度选择性。另一种化合物对 ePepN 具有中等抑制作用，但在生理相关浓度下，对这种细菌酶相对于其哺乳动物同源物具有完全选择性。该策略被证明对鉴定进一步优化和开发的先导化合物很有用。
