Rational and experiment-guided peptide design for disease-related intrinsically disordered proteins

抄録

Intrinsically disordered regions (IDRs) of proteins are involved in many diseases. However, the flexible IDRs hinder the use of 3D structure-based drug design methods. Liquid droplets of aggregation-prone proteins with IDRs, which become hydrogels or form amyloid fibrils, are a potential target for drug discovery. In this presentation, I will introduce an experiment-guided protocol for characterizing the design grammar of peptides that can regulate droplet formation and aggregation of fused in sarcoma (FUS) (Sci. Rep. 2021). Then, I will introduce a rational design method to obtain a peptide that can bind an IDR using only protein sequence information (Sci. Rep. 2019; under revision). We applied the method to the disordered disordered domains of a tumor suppressor p53 and demonstrated the regulation of liquid droplet formation and DNA-binding function. The sequence-based design may be useful in targeting IDRs for therapeutic purposes.