Seite - (000296) - in Biomedical Chemistry: Current Trends and Developments

chemical biology and in drug discovery, different approaches to overcome their limitations are needed. There are several strategies available that can be utilized for the development of drugs that modulates the physiological events that are triggered by peptides. One common approach is high-throughput screening (HTS) of libraries of small molecules. This approach only considers the macromolecular target and can be utilized if the target is known and a suitable biochemical assay is available. Peptide-based therapeutics is another, currently growing, area that instead focuses on the biologically active peptide and aims to circumvent the limitation of peptides by introducing various modifications (e.g. PEG and phosphoesters linkages) or by employing different ways of administration (e.g. parenteral, mucosal, oral and transdermal routes). As a complement to HTS and peptide modifications, rational design based on step-wise transformation of peptides into low-molecular- weight and bioavailable drug-like molecules that mimic the action of peptides, i.e. peptidomimetics, is a viable way to overcome the problems associated with peptides (Hruby, 2002; Olson, 1993; Ripka, 1998; Vagner, 2008). Peptidomimetics are molecules with significantly reduced peptide character that mimic the bioactive conformation of peptides, and thus retain the ability to interact with the biological target and cause the same biological effect (Grauer, 2009). As these compounds are non-peptides which often possess desired improved pharmacokinetic properties, such as better absorption, metabolic stability and/or bioavailability. There are several successful examples where a rational design approach has resulted in approved drugs, e.g. the development of protease inhibitors such as angiotensin-converting enzyme (ACE) inhibitors, HIV protease inhibitors, and hepatitis C virus (HCV) inhibitors. 3.3.1.1 Strategy for the Development of Peptidomimetics To transform biologically active peptides into small drug-like pseudopeptides or peptidomimetics in a rational way, a stepwise procedure, similar to the one outlined in Fig. 3.3.2, can be employed. Biological evaluation (both in vitro and in vivo), evaluation of