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The Remarkable Stability of Chimeric, Sialic Acid‐derived α/δ‐Peptides in Human Blood Plasma
Author(s) -
Saludes Jonel P.,
Natarajan Arutselvan,
DeNardo Sally J.,
GervayHague Jacquelyn
Publication year - 2010
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2010.00954.x
Subject(s) - sialic acid , chemistry , human plasma , biochemistry , human blood , chromatography , biology , physiology
Peptides are labile toward proteolytic enzymes, and structural modifications are often required to prolong their metabolic half‐life and increase resistance. One modification is the incorporation of non‐α‐amino acids into the peptide to deter recognition by hydrolytic enzymes. We previously reported the synthesis of chimeric α/δ‐peptides from glutamic acids (Glu) and the sialic acid derivative Neu2en. Conformational analyses revealed these constructs adopt secondary structures in water and may serve as conformational surrogates of polysialic acid. Polysialic acid is a tumor‐associated polysaccharide and is correlated with cancer metastasis. Soluble polysialic acid is rapidly cleared from the blood limiting its potential for vaccine development. One motivation in developing structural surrogates of polysialic acid was to create constructs with increased bioavailability. Here, we report plasma stability profiles of Glu/Neu2en α/δ‐peptides. DOTA was conjugated at the peptide N ‐termini by solid phase peptide synthesis, radiolabeled with 111 In, incubated in human blood plasma at 37 °C, and their degradation patterns monitored by cellulose acetate electrophoresis and radioactivity counting. Results indicate that these peptides exhibit a long half‐life that is two‐ to three‐orders of magnitude higher than natural α‐peptides. These findings provide a viable platform for the synthesis of plasma stable, sialic acid‐derived peptides that may find pharmaceutical application.