7f32

Ny-Hydroxyasparagine: A Multifunctional Unnatural Amino Acid That is a Good P1 Substrate of Asparaginyl Peptide Ligases

spinqualitylabelsall models 7f32 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7f32 is a 1 chain structure with sequence from Macaca mulatta. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, 9 models Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Peptidyl asparaginyl ligases (PALs) are powerful tools for peptide macrocyclization. Herein, we report that a derivative of Asn, namely N(gamma) -hydroxyasparagine or Asn(OH), is an unnatural P1 substrate of PALs. By Asn(OH)-mediated cyclization, we prepared cyclic peptides as new matrix metalloproteinase 2 (MMP2) inhibitors displaying the hydroxamic acid moiety of Asn(OH) as the key pharmacophore. The most potent cyclic peptide (K(i) =2.8+/-0.5 nM) was built on the hyperstable tetracyclic scaffold of rhesus theta defensin-1. The Asn(OH) residue in the cyclized peptides can also be readily oxidized to Asp. By this approach, we synthesized several bioactive Asp-containing cyclic peptides (MCoTI-II, kB2, SFTI, and integrin-targeting RGD peptides) that are otherwise difficult targets for PAL-catalyzed cyclization owing to unfavorable kinetics of the P1-Asp substrates. This study demonstrates that substrate engineering is a useful strategy to expand the application of PAL ligation in the synthesis of therapeutic cyclic peptides. N(gamma) -Hydroxyasparagine: A Multifunctional Unnatural Amino Acid That is a Good P1 Substrate of Asparaginyl Peptide Ligases.,Xia Y, To J, Chan NY, Hu S, Liew HT, Balamkundu S, Zhang X, Lescar J, Bhattacharjya S, Tam JP, Liu CF Angew Chem Int Ed Engl. 2021 Oct 4;60(41):22207-22211. doi: , 10.1002/anie.202108125. Epub 2021 Sep 9. PMID:34396662 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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