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1.
Chemistry ; 29(31): e202300111, 2023 Jun 02.
Article in English | MEDLINE | ID: mdl-36945747

ABSTRACT

Somatostatin (somatotropin release-inhibiting factor, SRIF) is a growth hormone inhibitory factor in the form of a 14- or 28-amino acid peptide. SRIF affects several physiological functions through its action on five distinct SRIF receptor subtypes (sst1-5). Native SRIF has only limited clinical applications due to its rapid degradation in plasma. To overcome this obstacle, we have developed glycosylated SRIF analogues that possess not only metabolic stability but also high affinity to all five receptor subtypes by attaching human complex-type oligosaccharides. Such glycosylated SRIF analogues with improved pharmacokinetic profiles could be potent and novel therapeutic drugs for SRIF-related diseases in which several SRIF receptor subtypes are closely involved, and also shed light on new indications. Our results show that chemical glycosylation can be a powerful tool for the development of peptide and protein analogues superior to the original molecules with enhanced drug properties.


Subject(s)
Receptors, Somatostatin , Somatostatin , Humans , Receptors, Somatostatin/metabolism , Glycosylation , Somatostatin/metabolism , Polysaccharides
2.
J Am Chem Soc ; 134(12): 5428-31, 2012 Mar 28.
Article in English | MEDLINE | ID: mdl-22404596

ABSTRACT

Chemical synthesis of homogeneous human glycoproteins exhibiting bioactivity in vivo has been a challenging task. In an effort to overcome this long-standing problem, we selected interferon-ß and examined its synthesis. The 166 residue polypeptide chain of interferon-ß was prepared by covalent condensation of two synthetic peptide segments and a glycosylated synthetic peptide bearing a complex-type glycan of biological origin. The peptides were covalently condensed by native chemical ligation. Selective desulfurization followed by deprotection of the two Cys(Acm) residues gave the target full-length polypeptide chain of interferon-ß bearing either a complex-type sialyl biantennary oligosaccharide or its asialo form. Subsequent folding with concomitant formation of the native disulfide bond afforded correctly folded homogeneous glycosyl-interferon-ß. The chemically synthesized sialyl interferon-ß exhibited potent antitumor activity in vivo.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Interferon-beta/chemical synthesis , Interferon-beta/therapeutic use , Amino Acid Sequence , Animals , Antineoplastic Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Glycosylation , Humans , Interferon-beta/chemistry , Mice , Models, Molecular , Molecular Sequence Data , Neoplasms/drug therapy , Xenograft Model Antitumor Assays
3.
Carbohydr Res ; 343(8): 1333-45, 2008 Jun 09.
Article in English | MEDLINE | ID: mdl-18395704

ABSTRACT

The assignment of (1)H and (13)C NMR signals of a complex type triantennary asialooligosaccharide was examined using 2D selective-TOCSY-DQFCOSY and HSQC-TOCSY experiments. The 2D selective-TOCSY-DQFCOSY experiment exhibits a 2D DQFCOSY spectrum of an individual monosaccharide in the undecasaccharide, although the NMR signals of several monosaccharides in the triantennary undecasaccharide are heavily overlapped. Selective excitation of each anomeric proton signal and subsequent TOCSY experiment afforded transverse magnetization corresponding to all of the proton signals of the monosaccharide. This magnetization was then developed with the corresponding DQFCOSY pulse sequence to afford the DQFCOSY spectrum of the individual monosugars. In this case, four GlcNAc-b, -e, -j, and -h residues were excited as a mixture. In order to assign (13)C signals, a conventional 2D HSQC-TOCSY spectrum was examined and compared with an unambiguous assignment of 2D selective-TOCSY-DQFCOSY thus obtained. This systematic analysis made it possible to obtain an assignment of the (1)H and (13)C NMR signals of the triantennary undecasaccharide. In addition, these experiments also revealed all of the glycosyl positions in the triantennary undecasaccharide.


Subject(s)
Asparagine/chemistry , Magnetic Resonance Spectroscopy , Oligosaccharides, Branched-Chain/chemistry , Acetylglucosamine/chemistry , Carbohydrate Conformation , Carbohydrate Sequence , Galactose/chemistry , Mannose/chemistry , Mannosides/chemistry , Molecular Sequence Data , alpha-Fetoproteins/chemistry
4.
Glycoconj J ; 21(5): 243-50, 2004.
Article in English | MEDLINE | ID: mdl-15486456

ABSTRACT

Partial sialyl transfer reaction by alpha-(2,3)-sialyltransferase toward (Gal-beta-1,4-GlcNAc-beta-1,2-Man-alpha-1,6/1,3-)(2)Man-beta-1,4-GlcNAc-beta-1,4-GlcNAc-beta-1-asparagine-Fmoc 1 was examined to obtain mono-alpha-(2,3)-sialyloligosaccharides and then branch-specific exo-glycosidase digestion (beta-D-galactosidase, N -acetyl-beta-D-glucosaminidase and alpha-D-mannosidase) toward the asialo-branch was performed to obtain diverse asparagine-linked complex type alpha-(2,3)-sialyloligosaccharides. In addition, two kinds of disialyloligosaccharides in which the sialyl linkage was a mixture of alpha-(2,3)- and alpha-(2,6)-types were also specifically prepared by an additional alpha-(2,6)-sialyltransferase reaction toward mono-alpha-(2,3)-sialyloligosaccharides thus obtained.


Subject(s)
Asparagine/chemistry , Oligosaccharides/chemical synthesis , Sialyltransferases/metabolism , Animals , Carbohydrate Conformation , Chromatography, High Pressure Liquid , Glycoside Hydrolases/metabolism , Neisseria meningitidis/enzymology , Oligosaccharides/chemistry , Rats , Recombinant Proteins , beta-Galactoside alpha-2,3-Sialyltransferase
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