Azapeptides as Pharmacological Agents

Abstract

Azapeptides, formed by replacing the C α of amino acid residues by nitrogen, are promising peptidomimetic compounds. Azaamino acids impart a unique conformational property to peptide structures because of the loss of chirality and reduction of flexibility of the parent linear peptide. The peculiar conformational properties make azaamino acids an attractive tool for drug design involving specific secondary structures in peptides and proteins. Additionally, since azapeptides are less susceptible to enzymatic breakdown by proteases, they may possibly lead to orally active drugs with longer duration of action. One of the advantages of azapeptides is their unproblematic synthesis allowing retention of the amino acid side chain. Azapeptides have been developed by several groups for the design of hormone analogues, protease inhibitors and active site titrants.

Hsp70 and gama-Semino protein as possible prognostic marker of prostate cancer

“…The β-lactam compounds have been considered a possible inhibitor for the elevated expression of gama-SM protein, however, the compounds are not very effective and may produce off-target inhibitory activity, which could point to adverse side effects (65). Another inhibitor that seems to have potentially greater capabilities than β -lactam is Azapeptides, which can constrain cysteine and serine proteases (66, 67). Azapeptides have been modified and tested to obstruct gama-SM protein.…”

Solution‐phase submonomer diversification of aza‐dipeptide building blocks and their application in aza‐peptide and aza‐DKP synthesis

“…Investigations in peptide mimicry have also shown that certain structural changes, when introduced into a peptide, can prevent enzyme degradation and induce conformational preferences that mimic the biologically active secondary structure4. Among the modifications found in peptide mimicry, aza‐peptides, in which one or more residue is replaced by an aza‐amino acid5, have found promising utility in enhancing the drug‐like character of peptide candidates6, by increasing the duration of action7 and resistance to enzymatic degradation8, 9 (see Figure 1 for relevant examples). Furthermore, aza‐amino acid residues have been shown to stabilize β‐turn conformations in peptides as detected by computational10–12, spectroscopic13–15 and crystallographic analyses13.…”

Inhibitors and Antibody Fragments as Potential Anti-Inflammatory Therapeutics Targeting Neutrophil Proteinase 3 in Human Disease

“…Azapeptides are peptide analogs in which one or more a-carbon atoms have been replaced by a nitrogen atom (Proulx et al, 2011). They can act as protease inhibitors when the replacement affects the a-carbon of the P1 residue in peptide analogs (Adessi and Soto, 2002;Zega, 2005). Azapeptides for the use as protease inhibitors generally contain a P1 aza-amino acid residue and a good reactive leaving group (-ONp, -OCH 2 CF 3 , -OPh), so that they form with the target protease a stable acyl-enzyme intermediate that dissociates very slowly (Zega, 2005).…”

“…They can act as protease inhibitors when the replacement affects the a-carbon of the P1 residue in peptide analogs (Adessi and Soto, 2002;Zega, 2005). Azapeptides for the use as protease inhibitors generally contain a P1 aza-amino acid residue and a good reactive leaving group (-ONp, -OCH 2 CF 3 , -OPh), so that they form with the target protease a stable acyl-enzyme intermediate that dissociates very slowly (Zega, 2005). The substitution of a carbon by a nitrogen atom at P1 decreases the electrophilicity of the P1 carbonyl group and also moves the geometry of the complex away from a tetrahedron.…”

“…The acyl derivative is a carbazate and is much more stable toward nucleophilic attack by water than the ester formed with substrates. The majority of azapeptides that inhibit serine proteases, including HNE, are peptide-nitrophenyl esters that release 4-nitrophenol when the acyl-enzyme complex is formed (Powers et al, 1984;Zega, 2005). Azapeptides containing a poor leaving group cannot acylate target proteases but simply act as reversible inhibitors (Dorn et al, 1977).…”