Recent Advances in the Synthesis and Applications of Reduced Amide Pseudopeptides

Abstract

Being one of the simplest and widely used isosteric replacements for the peptide bond, reduced amide has been successfully applied in the synthesis of many bioactive compounds. The introduction of reduced amide not only confers the pseudopeptide a higher enzymatic resistance and a linear and more flexible structure, but also increases its hydrophylicity due to the introduction of a protonable group. It has also proved adequate as a transition state mimetic for the tetrahedral intermediate formed during the hydrolysis of the peptide bond. Recent advances in the solution and solid-phase synthesis of reduced amides that emerged during the past ten years are presented. Most of them include the use of microwave irradiation to shorten the reaction times and improve the yields. The bioorganic chemistry of reduced-peptide-containing compounds represents an area of growing interest and it has recently been expanded to include analogues of endogenous peptides/ hormones that are resistant to hydrolysis by serum peptidases and enzyme inhibitors. Under certain conditions, synthetic peptides are highly immunogenic in animals, and might constitute chemically defined, safe and cheap vaccines. Linear pseudooligolysines, containing multiple adjacent CH2NH amide bond are potential candidates for future use as DNA carriers in gene delivery. Reduced amides have also seen use in the preparation of peptide nucleic acids and antibacterial peptides.

Modulation of lipid membrane structural and mechanical properties by a peptidomimetic derived from reduced amide scaffold

“…Peptidomimetics containing reduced amide bonds have been shown to exhibit superb resistance to enzymatic degradation [15]. The unique properties offered by reduced amide have inspired a wave of interests in the field of biology and medicine [16–19].…”

Small Antimicrobial Agents Based on Acylated Reduced Amide Scaffold

“…31 Even with one amide bond reduced to give secondary amine, the peptide sequences display significantly enhanced resistance to enzymatic degradation in contrast to canonical peptides. 31 Recently there is growing interest in the exploration of biological application of reduced- amide-containing compounds, such as the use as enzyme inhibitors, 32 analogues of endogenous peptides, 33 synthetic vaccines, 34 and DNA-complexing agents for gene delivery. 35 Several reduced-amide-containing sequences were also reported to mimic HDPs, as they are more resistant to proteolytic degradation.…”

A Reduced-Amide Inhibitor of Pin1 Binds in a Conformation Resembling a Twisted-Amide Transition State

“…(19) The broad use of reduced amide peptide isosteres in the design and synthesis of enzyme inhibitors has been reviewed. (20) To our knowledge, reduced amides have not yet been used as PPIase inhibitors. We now present pSer-Pro reduced amides 1, 2, 3 , and 4 designed as transition-state analogue inhibitors of the PPIase activity of Pin1.…”