Synthetic peptides, conjugation reagents and methods

Details Synthetic peptides, conjugation reagents and methods Synthetic peptides, conjugation reagents and methods

1999-09-23

2002-10-15

Carlson, Karen Cochrane (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

C530S305000, C530S326000, C530S327000, C514S002600, C514S012200, C514S013800, C514S014800, C514S023000, C514S025000, C514S042000, C435S325000, C536S018600, C560S019000

Reexamination Certificate

active

06465612

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to methods and reagents used to make synthetic peptide conjugates.
BACKGROUND OF THE INVENTION
Glycoprotein pharmaceuticals are major targets of the biotechnology industry and include such widely used therapeutic agents as tissue plasminogen activator (TPA), erythropoietin (EPO) and monoclonal antibodies. Glycosylation presents special challenges in drug discovery and development, largely due to the heterogeneity of oligosaccharide structures obtained from recombinant expression in eukaryotic cell lines. The presence of heterogeneous glycoforms convolutes the characterization of the glycoprotein's structure and biological activity, which hinders clinical evaluation and approval. New strategies for their production which control oligosaccharide structure and uniformity would facilitate the development of glycoprotein pharmaceutical agents.
We have developed novel methods for the synthesis of glycopeptides based on the highly selective reaction of nucleophilic carbohydtrate derivatives with ketone-containing peptides. Peptides bearing unnatural ketone side chains can be generated using N-protected (2S)-aminolevulinic acid by standard solid-phase peptide synthesis (SPPS). Oligosaccharides functionalized at their reducing termini with aminooxy, hydrazide or thiosemicarbazide groups can be coupled to keto-peptides in aqueous solvent without need for protecting groups or auxiliary coupling reagents. These methods can be used to prepare glycopeptides of therapeutic interest.
SUMMARY OF THE INVENTION
The invention provides methods and compositions useful for making synthetic peptide conjugates. In one embodiment, the invention provides compositions comprising the structure:
wherein R is selected from lower substituted or unsubstituted alkyl, O, NH and S and P is an amine protection group. In more particular embodiments, the compositions comprise &agr;-amine protected 4,5-dehydroleucine or &agr;-amine protected (2S)-aminolevulinic acid and/or P is F-moc. These compounds may be incorporated into a wide variety of synthetic molecules such as peptides. In a particular embodiment, such peptides comprise a substituted or unsubstituted (2S)-aminolevulinic acid residue, such as (2S)-aminolevulinic acid residue is substituted with an O- or N-linked glycoconjugate, or a detectable label. These peptides may be synthesized in vitro or in vivo and may be incorporated into cells or cellular structures.
The invention also provides methods for conjugating a molecule to a composition comprising a (2S)-aminolevulinic acid residue comprising the step of reacting the molecule with the residue under conditions whereby the molecule is covalently conjugated to residue. In particular embodiments, the composition comprises a synthetic peptide comprising the (2S)-aminolevulinic acid residue or the molecule is a glycoconjugate or comprises a detectable label.
DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS OF THE INVENTION
The following descriptions of particular embodiments are offered by way of illustration and not by way of limitation. Unless contraindicated or noted otherwise, in these descriptions and throughout this specification, the terms “a” and “an” mean one or more, the term “or” means and/or.


REFERENCES:
patent: 4692439 (1987-09-01), Rideout et al.
Yu, Zhonghua et al. Irreversible Inhibition of the HIV-1 Protease: Targeting Alkylating Agents to the Catalytic Aspartate Groups. J. Am. Chem. Soc, vol. 118, 1996 pp. 5846-5856, see Scheme 3.
Schmidt, Ulrich et al. The Synthesis of Epnemycin. J. Chem. Soc., Chem. Commun., 1992 pp. 529-530, see Scheme 1.

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