engleski

Solid phase synthesis of cycles peptides containing sugar amino acid

Peptides and proteins are compounds of major importance in a wide range of biological processes. Their development toward a commercial drug is very interesting, challenging, and time consuming process. Unfortunately, most of the linear peptides are not applicable as therapeutics because of their enzymatic instability, and difficulties in transport through the cell membranes and the blood-brain barriers. Their flexibility allows interactions with variety of receptors resulting in undesirable side effects. Cyclization as one of the peptide modifications results in higher stability to the enzymatic degradation and enables clinical application of the peptides. Incorporation of a specific component such as sugar molecule to the cyclic peptide affects the metabolic stability, hydrophilicity and lipophilicity of the molecule, contributing to the rigidity of conformation, and modifying affinity to the receptors. Muramic acid, a sugar amino acid, was chosen as a building block for incorporation in the cyclic peptide skeleton which contains biologically active sequence LSKL, responsible for the activation of TGF-β, and regulation of the signal pathway. Cyclic glycopeptide 1 was synthesized using standard Fmoc solid-phase peptide synthesis. First was prepared appropriate protected derivative of the muramic acid as sugar amino acid suitable for Fmoc strategy. Synthesis of linear glycopeptide was obtained using Fmoc protected amino acid and HBTU/HATU coupling reagents on instrument for peptide synthesis. Cyclic glycopeptide was prepared from linear precursor by so called, head-to-tail cyclization with PyBOP/HOBt/DIEA manually in the reaction vessel. The deprotection of the side chains of amino acids and cleavage from the resin of resulting peptide was achieved in one step under acidic conditions followed by deprotection of benzyl and benzylidene protecting groups from muramic acid under catalytic hydrogenation. Prepared cyclic glycopeptide was purified by reversed phase high-performance liquid chromatography (RP-HPLC).

cyclic peptides ; sugar amino acids ; solid phase peptide synthesis

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