Page - (000252) - in Biomedical Chemistry: Current Trends and Developments

because of rapid degradation by proteolytic enzymes of the digestive system and blood plasma, (iii) rapid removal from the circulation by the liver or kidneys, and (iv) high synthetic and production costs (Bray, 2003; Picherean & Allary, 2005). However, therapeutic peptides are becoming increasingly attractive for the discovery and development of new generations of drugs. With the recent addition of new methodologies, peptides can be engineered to have long plasma half-lives and low immunogenicity (Salo, 2006), along with alternative routes of administration. Production of synthetic therapeutic peptides has become possible for the pharmaceutical industry with recent developments of SPPS, initially developed by Merrifield. SPPS is crucial in the early steps of preclinical research and in the production of peptide-based active pharmaceutical ingredients (APIs) (Bruckdorfer, 2004). SPPS is especially suited for medium-sized peptides (up to 80 amino acids residues), which comprise the majority of therapeutically-relevant peptides. 3.1.3.4.1 Chemical Strategies to Improve Peptide Biological Activity To develop a peptide as a therapeutic agent, the crucial parameters to consider are its biological effect, pharmacokinetic profile and low immunogenicity. Various chemical strategies have been developed to try and overcome the limitations of peptides by increasing in vivo plasma residence time (Table 3.1.4) (Vlieghe, 2010). The chemical optimization strategy of a therapeutic peptide is based on structure-activity relationship (Witt, 2001; Ladner, 2004; Wittand & Davis, 2006) with the aim of improving bioavailability, reducing elimination and biodegradation as well as increasing selectivity or affinity to its target or receptor. According to Lipinski’s rule of five (Lipinski, 1997; 2000; 2004), completed by Veber analysis (Veber, 2002), peptides are poor candidates to move from the digestive tract to the circulatory system based on their physicochemical properties. Until a few years ago, therapeutic peptides were generally administered by subcutaneous, intramuscular or intravenous routes to circumvent the gut barrier. When administered orally, peptides have to face a strongly acidic gastric environment, high levels of intestinal proteolytic activity