Programming Nanostructure Formation Through Furin-Triggered Isopeptide Conversion and Peptide Self-Assembly.

The controlled bioresponsive formation of synthetic nanostructures requires the precise chemical design of precursor molecules that undergo stimulus-induced chemical conversion and subsequent self-assembly. In this study, we present an enzymeresponsive kinked isopeptide containing the recognition sequence RVRR of the protease furin, an enzyme that is overexpressed in many cancers. Despite the unnatural kinked structure of the isopeptide, we show that it is enzymatically cleaved, causing its rearrangement into a linear peptide capable of forming fibrillar nanostructures. We investigate the kinetics of this enzymatic transformation and compare it to a non-cleavable control isopeptide bearing a scrambled RRRV sequence. The material properties of the linear fiber-forming peptide are characterized using circular dichroism spectroscopy, fluorescence, and electron microscopy, as well as nuclear magnetic resonance spectroscopy. This study provides insights into the furin-induced transformation of a kinked isopeptide for the controlled formation of nanostructures and highlights the potential of enzyme-triggered isopeptide systems for the design of functional materials.