Major advances in the hydrolysis of peptides and proteins by metal ions and complexes

Metal ions and complexes that hydrolyze peptides and proteins have become increasingly important in recent years. These reagents have shown great promise for use in a variety of applications including protein sequencing and proteomics. When metal-assisted hydrolytic cleavage is accomplished under nondenaturing conditions of temperature and pH, their use can be extended to include the study of protein function and solution structure, the generation of semisynthetic proteins, the proteolytic cleavage of bioengineered fusion proteins, and therapeutics. Yet, because of the extreme stability of the peptide amide bond, hydrolytically active metals are limited in number and there is now great interest in the development of new, more efficient reagents. In this review, we provide a description of relevant, early work with metal ions and complexes that have been used to hydrolyze unactivated peptide amide bonds in peptides and proteins. More importantly, we present an overview of recent contributions that have been made toward the development of synthetic metal loproteases that catalyze hydrolysis under near physiological conditions of temperature and pH.