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PreprintCC BY-NC-NDChemRxiv

Flat Amino Acid Surrogates Induce Turn Conformers: Synthesis, Nitrogen Chirality, Conformation and Biomedical Applications of N-Amino Triazolone (Nat) Peptides

  • Chitra P. Sadanandhan1,2
  • Ida Boccino1,2,3,4
  • Mukandila Mulumba
  • Renaud Binette
  • Guillaume
  • François
  • Francesco Merlino3,4
  • Pierre-Luc Boudreault
  • Felix Polyak
  • Huy Ong
  • Willam D. Lubell1,2
4 affiliations
  1. 1Département de Chimie and §Faculté de Pharmacie
  2. 2Université de Montréal
  3. 3Department of Pharmacy
  4. 4University of Naples Federico II
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Abstract

4-Amino-1,2,4-triazol-3-ones are relatively flat but shown to serve as turn inducing amino amide surrogates in peptides. Model N-amino triazolone (Nat) peptides were first synthesized and shown by NMR studies in solution to exhibit diastereotopic glycine methylene protons indicative of chiral nitrogen with inversion barriers around 17-18 kcal/mol, as well as solvent shielded amide protons indicative of involvement in intramolecular hydrogen bonds in -turn conformers. In crystal structures packing forces likely perturbed intramolecular hydrogen bonding, but Nat residues exhibited dihedral angles characteristic of the i+1 central position of certain -turn structures. Introduction of Nat residues as turn surrogates into antimicrobial and anti-inflammatory peptide analogs gave respectively comparable activity against Gram positive and negative microorganisms as well as potent ability to mitigate Toll receptor agonist effects on cytokine and chemokine levels by the modulation of the cluster-of-differentiation-36 receptor (CD36) in

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Cite

BibTeXRIS
BibTeX
@misc{sadanandhan2026flat,
  title = {{Flat Amino Acid Surrogates Induce Turn Conformers: Synthesis, Nitrogen Chirality, Conformation and Biomedical Applications of N-Amino Triazolone (Nat) Peptides}},
  author = {Chitra P. Sadanandhan and Ida Boccino and Mukandila Mulumba and Renaud Binette and Guillaume and François and Francesco Merlino and Pierre-Luc Boudreault and Felix Polyak and Huy Ong and Willam D. Lubell},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15008420/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008420/v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Flat Amino Acid Surrogates Induce Turn Conformers: Synthesis, Nitrogen Chirality, Conformation and Biomedical Applications of N-Amino Triazolone (Nat) Peptides
AU  - Chitra P. Sadanandhan
AU  - Ida Boccino
AU  - Mukandila Mulumba
AU  - Renaud Binette
AU  - Guillaume
AU  - François
AU  - Francesco Merlino
AU  - Pierre-Luc Boudreault
AU  - Felix Polyak
AU  - Huy Ong
AU  - Willam D. Lubell
PY  - 2026
DA  - 2026/09/07
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15008420/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008420/v1
AB  - 4-Amino-1,2,4-triazol-3-ones are relatively flat but shown to serve as turn inducing amino amide surrogates in peptides. Model N-amino triazolone (Nat) peptides were first synthesized and shown by NMR studies in solution to exhibit diastereotopic glycine methylene protons indicative of chiral nitrogen with inversion barriers around 17-18 kcal/mol, as well as solvent shielded amide protons indicative of involvement in intramolecular hydrogen bonds in -turn conformers. In crystal structures packing forces likely perturbed intramolecular hydrogen bonding, but Nat residues exhibited dihedral angles characteristic of the i+1 central position of certain -turn structures. Introduction of Nat residues as turn surrogates into antimicrobial and anti-inflammatory peptide analogs gave respectively comparable activity against Gram positive and negative microorganisms as well as potent ability to mitigate Toll receptor agonist effects on cytokine and chemokine levels by the modulation of the cluster-of-differentiation-36 receptor (CD36) in
ER  -