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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ReplyDeleteStable isotope labeled peptides, maintain identical amino acid sequence with the natural ones released from the parent proteins by chemical or enzymatic cleavage, Stable Isotope Labeled Peptides
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