Michael acceptor peptidomimetics

Zedira designed peptidomimetic blockers bearing a michael acceptor pharmacophore.
The electrophilic α,β-unsaturated carbonyl compounds are attacked by the active site cysteine residue (1) to form an irreversible complex (2,3).

Michael acceptor peptidomimetics meachanism

The peptidic lead compound Z013 (ZED754) was used to cocrystallize with tissue transglutaminase. The picture shows the binding mode to the active site. The scaffold was subsequently optimized using medicinal chemistry.
Our clinical candidate ZED1227 is the first TG inhibitor in the clinics.
Compound ZED1301 (A108) is a potent FXIII inhibitor.


Structure of inhibited tissue transglutaminase
Structure of inhibited tissue transglutaminase.
The inhibitor (shown in cyan) is covalently bound by a Michael addition reaction to the active site Cys 277 (yellow surface), which is located in the catalytic tunnel. It mimics the peptide substrates. The main part of the inhibitor fits onto the protein surface, forming several hydrogen bonds and stabilizing the open conformation
(Lindemann et al., XX Int. Med.Chem. Symp. 2008).


Art. No.
Name
Quantity
Price
A108 Ac-(D)-Asp-MA-Nle-Nle-Leu-Pro-Trp-Pro-OH, "ZED1301"
5 mg
480 €
B015 Biotin-Ahx-MA-QPL-OMe
10 mg
480 €
Z013 Z-MA-QPL-OMe
10 mg
480 €

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    • Press release: Dr. Falk Pharma and Zedira announce completion of phase 1b clinical trial of ZED1227 for the treatment of celiac disease and move on to proof of concept study
    • Pressemitteilung: Dr. Falk Pharma und Zedira geben den Abschluss der Phase 1b-Studie für ZED1227 zur Zöliakie-Therapie bekannt und planen Start der Wirksamkeitsstudie
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    • Transglutaminases in Medicine

      03.08.2017 - 05.08.2017
      Debrecen, Hungary

    • 15th Congress on Amino Acids, Peptides and Proteins

      07.08.2017 - 11.08.2017
      Vienna, Austria

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      08.09.2017 - 10.09.2017
      New Delhi, India

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      06.11.2017 - 08.11.2017
      Berlin, Germany

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      13.11.2017 - 16.11.2017
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    • Gordon Research Conference on: Transglutaminases in Human Disease Processes

      16.06.2018 - 17.06.2018
      Les Diablerets, Switzerland