Solution Phase Conformation and Proteolytic Stability of Amide-Linked Neuraminic Acid Analogues

• Published in: Biopolymers Vol. 99; no. 10; pp. 686 - 696
• Main Authors: Saludes, Jonel P., Gregar, Travis Q., Monreal, I. Abrrey, Cook, Brandan M., Danan-Leon, Lieza M., Gervay-Hague, Jacquelyn
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.10.2013
• Subjects: 1,3‐dipolar cycloaddition chemistry; 3-dipolar cycloaddition chemistry; Amides - chemistry; Amino Acid Sequence; blood serum; Circular Dichroism; click chemistry; helical peptide; Humans; Molecular Sequence Data; Neu2en; NMR; Protein Conformation; Protein Structure, Secondary; proteolysis; sialic acid; Solutions; water-soluble scaffold; 1,3-dipolar cycloaddition chemistry; helical peptide; NMR; Neu2en; sialic acid; water-soluble scaffold; blood serum; click chemistry; circular dichroism; proteolysis
• ISSN: 0006-3525; 1097-0282
• DOI: 10.1002/bip.22315

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. © 2013 Wiley Periodicals, Inc. Biopolymers 99: 686–696, 2013.