Combinatorial Multicomponent Access to Natural‐Products‐Inspired Peptidomimetics: Discovery of Selective Inhibitors of Microbial Metallo‐aminopeptidases
Citations Over TimeTop 22% of 2014 papers
Abstract
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.
Related Papers
- → Solid‐Phase Synthesis of Peptidomimetics with Peptide Backbone Modifications(2021)20 cited
- → A hierarchical approach to peptidomimetic design(1993)152 cited
- → Peptide and peptidomimetic libraries(1998)25 cited
- → One-Pot High-Throughput Synthesis of β-Turn Cyclic Peptidomimetics via “Volatilizable” Supports(2009)7 cited
- → Synthesis and Properties of New Fluorinated Peptidomimetics(2005)3 cited