Discovery of Natural Product Analogues with Altered Activities by a High-Throughput Strategy

Abstract

To exploit natural products as a source of biologically active compounds, accelerating the discovery of analogues that exhibit more potent and modulated biological activities is essential. In this chapter, two specific examples of a one-bead-one-compound (OBOC)-based functional enhancement and modulation of peptidic natural products are demonstrated. As structurally distinct natural product scaffolds, macrocyclic lysocin E and linear gramicidin A were adopted. The combination of solid-phase synthesis with a split-and-mix approach, microscale functional evaluation, and structure determination based on tandem mass spectrometry led to the successful discovery of natural product analogues that exhibited enhanced and altered functions. These results exemplify the potential of this strategy for accelerating the structure–activity relationship study and structural optimization of natural products.