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Solution Phase Conformation and Proteolytic Stability of Amide‐Linked Neuraminic Acid Analogues
Author(s) -
Saludes Jonel P.,
Gregar Travis Q.,
Monreal I. Abrrey,
Cook Brandan M.,
DananLeon Lieza M.,
GervayHague Jacquelyn
Publication year - 2013
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22315
Subject(s) - chemistry , amide , sialic acid , combinatorial chemistry , neuraminic acid , peptide , stereochemistry , peptide bond , circular dichroism , protein secondary structure , solid phase synthesis , ring (chemistry) , organic chemistry , biochemistry
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. © 2013 Wiley Periodicals, Inc. Biopolymers 99: 686–696, 2013.