Often originating from natural products, peptide-based macrocycles are an important topological class of molecules that are common place in commercial therapeutics. With the rise of antibiotic resistance in bacterial strains, an undeniable need for novel, potent antimicrobial agents has become apparent. Here, we report two simple and effective methods for the formation of biomimetic peptide macrocycles via rapid, efficient hydrazone condensation. Aldehyde and acyl hydrazide functionalities were incorporated using high yielding solid-phase copper catalyzed alkyne-azide cycloaddition (CuAAC) click reactions. Single, double, and triple loop peptide tertiary structures with highly tunable ring sizes can be formed selectively upon reaction of bis-hydrazide or aldehyde small molecules with di-, tetra-, or hexa- functionalized dynamic covalent (DC) peptides, respectively. Furthermore, using hydrazide functionalized resins, intra- and intermolecular peptide macrocycles were synthesized quantitatively following resin cleavage depending on the spacing of the clicked aldehyde group from the hydrazide terminus, as characterized by MALDI-TOF MS and SDS-PAGE. At high concentrations, nucleophilic catalysis using monohydrazides small molecules leads to the scrambling of macrocycles forming oligomeric, cyclic and linear sequence-defined polymers. The antibiotic activities of these cyclic peptide tertiary structures were assessed using high-throughput screening proving that these structures can be utilized as novel, antibiotic therapeutics. Overall, this method provides a new, efficient means to biologically relevant peptide macrocycles with topological diversity and hold great promise in the field of dynamic combinatorial chemistry.

Versatile, effective formation of biologically active single- and multi-loop peptide macrocycles via hydrazone condensation

253rd National Meeting (2017)

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