Translational aspect in peptide drug discovery and development: An emerging therapeutic candidate.

ABSTRACT

In the last two decades, protein-protein interactions (PPIs) have been used as the main target for drug development. However, with larger or superficial binding sites, it has been extremely difficult to disrupt PPIs with small molecules. On the other hand, intracellular PPIs cannot be targeted by antibodies that cannot penetrate the cell membrane. Peptides that have a combination of conformational rigidity and flexibility can be used to target difficult binding interfaces with appropriate binding affinity and specificity. Since the introduction of insulin nearly a century ago, more than 80 peptide drugs have been approved to treat a variety of diseases. These include deadly diseases such as cancer and human immunodeficiency virus infection. It is also useful against diabetes, chronic pain, and osteoporosis. Today, more research is being done on these drugs as lessons learned from earlier approaches, which are still valid today, complement newer approaches such as peptide display libraries. At the same time, integrated genomics and peptide display libraries are new strategies that open new avenues for peptide drug discovery. The purpose of this review is to examine the problems in elucidating the peptide-protein recognition mechanism. This is important to develop peptide-based interventions that interfere with endogenous protein interactions. New approaches are being developed to improve the binding affinity and specificity of existing approaches and to develop peptide agents as potentially useful drugs. We also highlight the key challenges that must be overcome in peptide drug development to realize their potential and provide an overview of recent trends in peptide drug development. In addition, we take an in-depth look at early efforts in human hormone discovery, smart medicinal chemistry and design, natural peptide drugs, and breakthrough advances in molecular biology and peptide chemistry.