Solution phase conformation and proteolytic stability of amide-linked neuraminic acid analogues

Jonel P. Saludes, Travis Q. Gregar, I. Abrrey Monreal, Brandan M. Cook, Lieza M. Danan-Leon, Jacquelyn Gervay-Hague

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Amide-linked homopolymers of sialic acid offer the advantages of stable secondary structure and increased bioavailability making them useful constructs for pharmaceutical design and drug delivery. Defining the structural characteristics that give rise to secondary structure in aqueous solution is challenging in homopolymeric material due to spectral overlap in NMR spectra. Having previously developed computational tools for heteroologomers with resolved spectra, we now report that application of these methods in combination with circular dichroism, NH/ND NMR exchange rates and nOe data has enabled the structural determination of a neutral, δ-amide-linked homopolymer of a sialic acid analogue called Neu2en. The results show that the inherent planarity of the pyranose ring in Neu2en brought about by the α,δ-conjugated amide bond serves as the primary driving force of the overall conformation of the homooligomer. This peptide surrogate has an excellent bioavailability profile, with half-life of ∼12 h in human blood serum, which offers a viable peptide scaffold that is resistant to proteolytic degradation. Furthermore, a proof-of-principle study illustrates that Neu2en oligomers are functionalizable with small molecule ligands using 1,3-dipolar cycloaddition chemistry.

Original languageEnglish (US)
Pages (from-to)686-696
Number of pages11
JournalBiopolymers
Volume99
Issue number10
DOIs
StatePublished - Oct 2013

Fingerprint

Neuraminic Acids
Amides
Conformations
N-Acetylneuraminic Acid
Homopolymerization
Peptides
Biological Availability
Acids
Nuclear magnetic resonance
Cycloaddition
Drug Design
Cycloaddition Reaction
Dichroism
Scaffolds (biology)
Circular Dichroism
Drug delivery
Oligomers
Scaffolds
Drug products
Half-Life

Keywords

  • 1,3-dipolar cycloaddition chemistry
  • blood serum
  • circular dichroism
  • click chemistry
  • helical peptide
  • Neu2en
  • NMR
  • proteolysis
  • sialic acid
  • water-soluble scaffold

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Biomaterials
  • Organic Chemistry

Cite this

Saludes, J. P., Gregar, T. Q., Monreal, I. A., Cook, B. M., Danan-Leon, L. M., & Gervay-Hague, J. (2013). Solution phase conformation and proteolytic stability of amide-linked neuraminic acid analogues. Biopolymers, 99(10), 686-696. https://doi.org/10.1002/bip.22315

Solution phase conformation and proteolytic stability of amide-linked neuraminic acid analogues. / Saludes, Jonel P.; Gregar, Travis Q.; Monreal, I. Abrrey; Cook, Brandan M.; Danan-Leon, Lieza M.; Gervay-Hague, Jacquelyn.

In: Biopolymers, Vol. 99, No. 10, 10.2013, p. 686-696.

Research output: Contribution to journalArticle

Saludes, JP, Gregar, TQ, Monreal, IA, Cook, BM, Danan-Leon, LM & Gervay-Hague, J 2013, 'Solution phase conformation and proteolytic stability of amide-linked neuraminic acid analogues', Biopolymers, vol. 99, no. 10, pp. 686-696. https://doi.org/10.1002/bip.22315
Saludes, Jonel P. ; Gregar, Travis Q. ; Monreal, I. Abrrey ; Cook, Brandan M. ; Danan-Leon, Lieza M. ; Gervay-Hague, Jacquelyn. / Solution phase conformation and proteolytic stability of amide-linked neuraminic acid analogues. In: Biopolymers. 2013 ; Vol. 99, No. 10. pp. 686-696.
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