Peptide Modifications to Increase Metabolic Stability and Activity Posted by R Santhosh Kalash on 10/20/2013 12:22:00 pm 2 comments

Historically, natural products have served as important sources of pharmacologically active compounds or lead structures for the development of new drugs. Among natural products, peptides are particularly interesting because of the key roles they play in biological processes. Peptides’ potential for high efficacy and their minimal side effects combined with advances in recombinant DNA technology, solid-phase synthetic chemistry, purification technology, and new strategies for peptide drug delivery made them widely considered as lead compounds in drug development. At present around 67 peptides are in the world market for clinical applications, some 270 are in clinical phases, and more than 400 are in advanced preclinical trials worldwide. Peptide-based therapeutics exist for a variety of human diseases, including osteoporosis (calcitonin), diabetes (insulin), infertility (gonadorelin), carcinoid tumors and acromegaly (octreotide), hypothyroidism (thyrotropinreleasing hormone [TRH]), and bacterial infections (vancomycin, daptomycin). However, despite their great potential, there are still limitations for peptides as drugs per se. Major disadvantages are short half-life, rapid metabolism, and poor permeation across biological barriers such as the blood–brain barrier (BBB) and intestinal mucosa. Nevertheless, pharmacokinetic properties of peptides can be improved and optimized through synthetic modifications. Peptidomimetic modifications, cyclization of linear peptides, or incorporation of D - and non-proteinogenic amino acids are traditionally used, both in academia and in industry, as an attractive method to provide more stable and bioactive peptides. In addition, linear peptide sequence modification by cyclization, glycosylation, and incorporation of non-proteinogenic amino acids have been widely used to enhance the potential of peptides as therapeutic agents. Peptide modifications to increase metabolic stability and activity is the first volume of a series that summarizes methods for preparation and purification of these peptides, and assessment of their biochemical activity. Readers of this volume will find detailed synthetic protocols that lead to modifications of the peptide backbone, side chains chapter, and terminal residues. Among these are protocols for preparation of conformationally constrained peptides (Chapters 1 and 2 ), modifi cation of peptide bonds (Chapters 3 and 4 ), introduction of non-proteinogenic amino acids (Chapters 5 – 7 ), and alteration of peptides’ physical and biological properties by modifi cation of the amino acid side chains and/or terminal residues (Chapters 8 – 12 ). Last chapter (Chapter 13 ) describes a new experimental approach for the detection of exogenous peptides within living cells using peptides labeled with heavy isotopes and confocal Raman microscopy. This method allows peptide structure–activity relationships and metabolism to be explored directly within the targeted cellular environment. Of course, there are many other ways to improve peptides’ metabolic stability and activity (e.g., peptide PEGylation or N -methylation of peptide bond and/or incorporation of D -amino acids) and they are well documented in the literature. However, my goal in this volume is to provide alternative approaches to peptide modification that many researchers may find applicable to their specific research requirements.

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