CHARACTERIZATION AND CONFIGURATIONAL ANALYSIS OF PEPTIDE CYCLOPHANES

Abstract

Peptide cyclophane natural products have received attention in drug discovery as the cyclophane unit has been found in many bioactive compounds such as vancomycin. In the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), enzymes of the radical S-adenosylmethionine (rSAM) superfamily have been shown to catalyze the formation of the carbon-carbon bonds which leads to various cyclophane macrocycles. We were interested in several bioinformatically predicted rSAM enzymes that could potentially catalyze a similar type of reaction. This thesis presents the characterization of the products from an rSAM enzyme which originated from Oscillatoriales cyanobacterium. Two novel peptides (compound 38 and 39) that contain characteristic tripeptide cyclophanes were isolated from heterologous coexpression of the enzyme and its respective precursor peptide. NMR-based predictions from the configurational analysis of the cyclophane units suggested that the new stereocenters adopt an (S) configuration. The new cyclophane scaffolds could be useful for drug developments.