7F32

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

Summary for 7F32

• Entry DOI: 10.2210/pdb7f32/pdb
• Descriptor: SYCNCLCRRGVCRCICTI (1 entity in total)
• Functional Keywords: structure from cyana 2.1, metal binding protein
• Biological source: Macaca mulatta
• Total number of polymer chains: 1
• Total formula weight: 2069.57

Authors

Xia, Y.,Liu, C.F. (deposition date: 2021-06-15, release date: 2022-09-07)

Primary citation

Xia, Y.,To, J.,Chan, N.Y.,Hu, S.,Liew, H.T.,Balamkundu, S.,Zhang, X.,Lescar, J.,Bhattacharjya, S.,Tam, J.P.,Liu, C.F.
N gamma-Hydroxyasparagine: A Multifunctional Unnatural Amino Acid That is a Good P1 Substrate of Asparaginyl Peptide Ligases.
Angew.Chem.Int.Ed.Engl., 60:22207-22211, 2021

PubMed Abstract: Peptidyl asparaginyl ligases (PALs) are powerful tools for peptide macrocyclization. Herein, we report that a derivative of Asn, namely N -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 =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.

PubMed: 34396662
DOI: 10.1002/anie.202108125

Experimental method

SOLUTION NMR