Peptide-Based Drug Design

13
Peptidomimetics: Fmoc Solid-Phase Pseudopeptide
Synthesis
Predrag Cudic and Maciej Stawikowski
Summary
Peptidomimetic modifications or cyclization of linear peptides are frequently used as
attractive methods to provide more conformationally constrained and thus more stable and
bioactive peptides. Among numerous peptidomimetic approaches described recently in the
literature, particularly attractive are pseudopeptides or peptide bond surrogates in which
peptide bonds have been replaced with other chemical groups. In these peptidomimetics
the amide bond surrogates possess three-dimensional structures similar to those of natural
peptides, yet with significant differences in polarity, hydrogen bonding capability, and acidbase
character. The introduction of such modifications to the peptide sequence is expected
to completely prevent protease cleavage of amide bond and significantly improve peptides’
metabolic stability.
In this chapter we consider Fmoc solid-phase synthesis of peptide analogs containing
the amide surrogate that tend to be isosteric with the natural amide. This includes
synthesis of peptidosulfonamides, phosphonopeptides, oligoureas, depsides, depsipeptides,
and peptoids.
Key Words: Peptidomimetics; pseudopeptides; isosteres; Fmoc solid-phase synthesis;
peptidosulfonamides; phosphonopeptides; oligourea; depsides; depsipeptides; peptoids.
1. Introduction
In recent years peptides have gained momentum as therapeutic agents.
According to Frost and Sullivan around 720 peptide drugs and drug candidates
were reported in 2004, among which 5% are already marketed worldwide, 1% in
registration, 38% in clinical trials, and 56% in advanced preclinical phases (1).
Peptides’ potential high efficacy combined with minimal side effects made them
From: Methods in Molecular Biology, vol. 494: Peptide-Based Drug Design
Edited by: L. Otvos, DOI: 10.1007/978-1-59745-419-3 13, © Humana Press, New York, NY
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