Improving stability of peptide drugs through chemical modifications
Potential for high efficacy and low toxicity coupled with advances in solid phase technology and purification methods have led to the wide acceptance of peptide based drugs in recent years. However, the development of peptide drugs is often hampered by limitations such as short half-life, rapid metabolism, proteolytic cleavage and poor permeation across biological membranes. Pharmacokinetics of peptides can be improved by chemical modifications during or after the peptide synthesis. This mini-review will focus on different methods of peptide modifications to increase the metabolic stability, bioavailability and pharmacokinetic properties of peptides. This will provide researchers with a comprehensive overview of methods and approaches that can be considered in drug discovery and development programs.
In the last few decades of scientific research, a large number of biologically active peptides have been discovered and knowledge of the structures, properties, and functions of these peptides has grown considerably (1, 2). Peptides have important roles in normal body functions as well as in disease physiology acting as hormones, neurotransmitters, antigens, modulators of cell surface receptors etc. Simple peptide structures have certain limitations to be developed and used as drugs. Enzymes rapidly degrade peptides by cleaving peptide bonds which ultimately leads to a loss of biological activity (3-5). Oral delivery of peptides is difficult due to the instability of amide bonds under physiological conditions. The gastrointestinal tract (GI) doesn’t promote the delivery of peptide drugs to target areas. Cellular peptidases from mucosal cells and the brush-border membranes of epithelial cells form a major enzymatic blockade to peptides (6). Exopeptidases, aminopeptidases and carboxypeptidases from GI tract breakdown the sequences from N- and C-terminals, whereas endopeptidases recognize cleavage sites within the amino acid linkages. The com ...