PEPscreen® — An Enabling Technology for Peptide-Based Drug Discovery
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Peptide-Based Drug Discovery
Successful drug discovery invariably involves protein studies, because most drugs are designed either to interact with specific target proteins, or to alter target protein-protein interactions. Conventional one protein-one experiment strategy is time consuming and expensive. Current approaches toward a successful lead development and drug discovery requires high throughput screening (HTS), that is, a fast and efficient screening of a large number of compounds in a parallel manner. High throughput screening is made possible as a result of the merging of three distinct technologies.
- Genomics and Proteomics – High throughput genomic analysis resulted in the identification of thousands of functionally important genes, with several of the protein products not isolated or identified. On the other hand, high throughput proteomic analysis resulted in the isolation and identification of a large number of proteins, but mostly with unknown functions. These dilemmas serve as driving forces to search for high throughput systems for identifying proteins and analyzing their structure and function relationships.
- Combinatorial Peptide Synthesis – Technologies that allow combinatorial synthesis of large libraries of different organic compounds are now available. Although combinatorial peptide synthesis platforms have been in existence for some time, the PEPscreen® platform is the first truly flexible system with the ability to incorporate non-standard amino acids, molecular dyes, isotopic labels, varied peptide lengths, and various numbers of peptides — all in a single run. This flexibility enables synthesis of a variety of peptide libraries and addresses drug discovery research in the framework of high throughput, parallel screening.
- Software Programming and Robotics – Advances in software programming and robotics enable automation in all aspects of drug discovery: in genomic and proteomic analysis, in the synthesis of peptide libraries and in high throughput functional assays. More importantly, software programming enables fast processing of extremely large amounts of data and customizing reports according to the experimental design.
Peptide-Based Drug Discovery
Proteins are large molecules and are usually ineffective as drugs due to delivery and stability issues. As a large molecule, a single protein may have multiple biological functions, where each function is defined by localized interactions of a specific sequence of amino acids in the protein with another protein or a non-protein ligand. A specific sequence of the protein that represents the active site is called an epitope. An epitope can be a continuous sequence of amino acids or discontinuous sequences that are in close proximity to each other in the three-dimensional protein structure. The first step in drug development is to “map” these active sequences of a protein in a process called epitope mapping (Figure 1). The purpose is to determine the minimum sequence of a peptide that constitutes the active domain of the protein, thus avoiding the inherent problems of delivering and stabilizing whole proteins as drug candidates. Once the epitope is identified the peptide sequence is then optimized and stabilized into a final drug product. Epitope mapping and sequence optimization involve the use of large numbers of peptides that constitute libraries, which are then synthesized and assayed in a parallel, high throughput manner.
Figure 1. General steps in peptide-based drug development. Each color represents a specific amino acid.
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