ABSTRACT
Protein-protein interactions(PPI)with large and shallow interfaces are generally undruggable targets. Many PPI in-volved in vital biological processes are mediated by helixes,therefore PPI can be easily targeted by helical epitope mimics. However, the application of peptide was limited by its conformational flexibility and low stability until the significant work was done by Arora ,et al who applied nucleation and crosslinking strategies to lock peptides in helical conformation. The conformation-locked strategies helps to improve peptide stability,cell permeability,and afterwards target intracellular PPI. At present,the conformation-locked strategies of peptides have achieved great development,and have become a hot spot in peptide research field. In this paper,the recent develop-ment,centering nucleation strategies,applications and bright prospects of helical conformation-locked peptides,are reviewed in order to provide theoretical basis for drug design based on PPI.
ABSTRACT
The potassium channel encoded by the human ether-a-go-go related gene (hERG) plays a very important role in the physiological and pathological processes in human. hERG potassium channel determines the outward currents which facilitate the repolarization of the myocardial cells. Some drugs were withdrawn from the market for the serious side effect of long QT interval and arrhythmia due to blockade of hERG channel. The strategies for lead compound optimization are to reduce inhibitory activity of hERG potassium channel and decrease cardiac toxicity. These methods include reduction of lipophilicity and basicity of amines, introduction of hydroxyl and acidic groups, and restricting conformation.