Synthesis and properties of the first all‐aza analogue of a biologically active peptide

Gante, Joachim; Krug, Michael; Lauterbach, G.; Weitzel, Reinhard; Hiller, W.

doi:10.1002/psc.310010307

Cited by 37 publications

(34 citation statements)

References 10 publications

(4 reference statements)

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“…There are numerous literature examples of the use of azapeptides as peptide mimetics, particularly as protease inhibitors and beta-turn inducing substitutions 235,236 but also as enzyme active sites titrants, 237±242 Leu-enkephalin, 243 eledoisin, 244 RGD mimetics, 245 and renin inhibitors. 246,247 Studies have demonstrated azapeptide resistance to amino-and carboxy-peptidases and they have also been used as prodrugs. 248 It has been recently shown that that the azapeptide conformational bias is neither disruptive to binding the MHC II protein nor to T-cell activation.…”

Section: D E S I G N O F P E P T I D E -M I M E T I C S T H a T Bmentioning

confidence: 99%

Binding interactions between peptides and proteins of the class II Major Histocompatibility Complex

McFarland

Beeson

2002

Medicinal Research Reviews

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The activation of helper T cells by peptides bound to proteins of the class II Major Histocompatibility Complex (MHC II) is pivotal to the initiation of an immune response. The primary functional requirement imposed on MHC II proteins is the ability to efficiently bind thousands of different peptides. Structurally, this is reflected in a unique architecture of binding interactions. The peptide is bound in an extended conformation within a groove on the membrane distal surface of the protein that is lined with several pockets that can accommodate peptide side-chains. Conserved MHC II protein residues also form hydrogen bonds along the length of the peptide main-chain. Here we review recent advances in the study of peptide-MHC II protein reactions that have led to an enhanced understanding of binding energetics. These results demonstrate that peptide-MHC II protein complexes achieve high affinity binding from the array of hydrogen bonds that are energetically segregated from the pocket interactions, which can then add to an intrinsic hydrogen bond-mediated affinity. Thus, MHC II proteins are unlike antibodies, which utilize cooperativity among binding interactions to achieve high affinity and specificity. The significance of these observations is discussed within the context of possible mechanisms for the HLA-DM protein that regulates peptide presentation in vivo and the design of non-peptide molecules that can bind MHC II proteins and act as vaccines or immune modulators.

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Section: D E S I G N O F P E P T I D E -M I M E T I C S T H a T Bmentioning

confidence: 99%

Binding interactions between peptides and proteins of the class II Major Histocompatibility Complex

McFarland

Beeson

2002

Medicinal Research Reviews

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“…Later they also investigated the influence of multiple aza-replacement in the same molecule on the biological activity and they synthesised an all-azaamino acid analogue of the peptide renin inhibitor. The rigidity caused by the aza moiety leads to poorer fitting into the binding site and therefore reduced activity [82].…”

Section: Protease Inhibitors and Active Site Titrantsmentioning

confidence: 99%

Azapeptides as Pharmacological Agents

Zega¹

2005

Current Medicinal Chemistry

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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.

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“…Moreover, after amidification of the carbazic acid chloride 10, the ester function of 11, 15 and 19 can be saponified into a carboxylic group (13,16) or converted into a carboxamide group by aminolysis (14a±c, 17a±c and 20), so giving access to the AzAsp or AzAsn residue. The carboxylic group in 16 also reacted with a secondary amine (dimethylamine) to give a N d ,N d -disubstituted AzAsn residue (18).…”

Section: Liquid-phase Aza-peptide Synthesismentioning

confidence: 99%

“…451, 1 rue Grandville, 54001 Nancy, France. 11,13]. However, coupling requires in both cases a high temperature and long reaction times, and often results in low yields with numerous side products such as phenolic derivatives, hydantoins [9,10] and oxadiazolones [4,12,14].…”

mentioning

confidence: 99%

Triphosgene: an efficient carbonylating agent for liquid and solid-phase aza-peptide synthesis. Application to the synthesis of two aza-analogues of the AChR MIR decapeptide

et al. 1997

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The N alpha/C alphaH exchange in aza-peptides has the advantage of preserving the side chain. Bis(trichloromethyl)carbonate or triphosgene is a solid, stable phosgene substitute which retains its high reactivity. Temperature and coupling times are greatly reduced with reference to other usually recommended carbonylating agents, while purity and yield are increased. It has been used, in both liquid- and solid-phase procedures, for the synthesis of various aza-analogues of dipeptides, tripeptides and decapeptides containing the alanine, aspartic acid and asparagine aza-residue.

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Synthesis and properties of the first all‐aza analogue of a biologically active peptide

Cited by 37 publications

References 10 publications

Binding interactions between peptides and proteins of the class II Major Histocompatibility Complex

Binding interactions between peptides and proteins of the class II Major Histocompatibility Complex

Azapeptides as Pharmacological Agents

Triphosgene: an efficient carbonylating agent for liquid and solid-phase aza-peptide synthesis. Application to the synthesis of two aza-analogues of the AChR MIR decapeptide

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