Polymers and polymer-peptide conjugates

Details Polymers and polymer-peptide conjugates Polymers and polymer-peptide conjugates

1990-06-04

1993-03-02

Nutter, Nathan M.

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

525 541, 530333, 530334, 530338, C07K 104, C07K 1708

Patent

active

051910152

DESCRIPTION:

BRIEF SUMMARY
This invention relates to insoluble polymer supports for use in peptide synthesis, to their use in peptide synthesis, and polymer-peptide conjugates.
It is known to use polymers as insoluble support matrices in peptide synthesis, oligonucleotide synthesis, oligosaccharide synthesis, catalysis applications, affinity chromatography, pharmaceutical applications and for enzyme immobilisation. The use of insoluble polymers as reagent supports in organic syntheses facilitates the separation of products and reagents and has other advantages.
The use of insoluble polymer supports has been of particular importance in the synthesis of peptides (see for example the Merrifield synthesis--Merrifield, R.B. (1962), Fed. Proc. Fed. Amer. Soc. Exp. Biol., 21, 412 and (1963), J. Amer. Chem. Soc., 85, 2149) and oligonucleotides (see for example Letsinger, R.L. and Kornet, M.J. (1963), J. Amer. Chem Soc., 85, 3045 and (1964), J. Amer. Chem. Soc., 86, 5163). The solid phase synthesis of peptides has been reviewed by a number of authors (see Meienhofer, J., (1973) in "Hormonal Proteins and Peptides", Ed. C.H. Li, 2, 45-267, Academic Press, New York; Erickson, B.W. et al (1976) in "The Proteins", Ed. H. Neurath et al, 2, 255-327, Academic Press, New York; and Barany, G. and Merrifield, R.B. (1980) in "The Proteins", Ed. E. Gross et al 3-284, Academic Press, New York).
The classical Merrifield method of polymer supported peptide synthesis was developed using insoluble cross-linked polystyrene supports. The supports are prepared by copolymerising divinylbenzene and styrene in suspension, to produce an insoluble beaded polymer. The peptide is synthesised on the insoluble support which facilitates separation of the desired produce (attached to the support) from the other reagents (in solution) and has other advantages. The polystyrene backbone remains largely chemically inert, although as the peptide chain grows, the swelling properties of the polymer may alter.
A development of the Merrifield method was proposed by Sheppard (Sheppard, R.C. (1971), in "Peptides 1971", Ed. H. Nesvadba, 111-125, North Holland, Amsterdam; Atherton, E., Clive, D.L.J., and Sheppard, R.C. (1975) J. Amer. Chem. Soc 97 6585) in which the non-polar polystyrene is replaced with a polar polymer, polydimethylacrylamide. Polydimethylacrylamide possesses similar solvation properties in polar solvents to those of a side chain protected peptide chain synthesised on the polymer. This minimises aggregation phenomena within the peptide-polymer matrix and may result in improved peptide quality and yield. The use of polydimethylacrylamide as a polymer support has been reviewed by Atherton et al (Atherton, E. et al (1979) Biorg. Chem., 8, 370. Peptide synthesis on insoluble cross-linked polydimethylacrylamide gels obtained by copolymerisation of dimethylacrylamide, acryloylsarcosine methyl ester and ethylene bisacrylamide is well established (Atherton E. et al, (1979) Biorg. Chem., 8, 351). Alternative polyamide supports have been described (Smith, C.W. et al (1979), Int. J. Peptide. Protein. Res., 13, 109; Stahl, G.L. et al (1979), J. Amer. Chem. Soc., 101, 5383; and Epton R. et al (1979), Polymer, 20, 1444). The polydimethylacrylamide resin has been prepared by suspension copolymerisation and used as a beaded gel in a batch process peptide synthesis (Arshady, R. et al, (1979). J.C.S., Chem. Comm., 423). More recently, copolymerisation of the monomers in the presence of an inert Kieselguhr support matrix has enabled the polymer support to be packed into a column and used in a continuous flow method of peptide synthesis (Atherton, E., Brown E., Sheppard, R.C., and Rosevear, A. (1981) J. Chem. Soc. Chem. Comm., 1151; Sheppard, R.C. (1983), Chem. Brit., 19, 402).
Peptides have been synthesised on "soluble polymer supports, such as polyethyleneglycol, to form a polymer-peptide conjugate molecule. Precipitation of the polymer-peptide conjugate by changing the solvent has been used to facilitate separation of the conjugate from by-products (Mutter et al, (1978) Angew. Chem. I

REFERENCES:
patent: 3700609 (1972-10-01), Tregear et al.
patent: 3737412 (1973-06-01), Wildi
patent: 4598122 (1986-07-01), Goldenberg
patent: 4923901 (1990-05-01), Koester et al.
Webb et al., JCS Perkin I, 1962, 125, pp. 4307-4319.
Arshady et al., JCS Perkin I, 1981, 538, pp. 529-537.
Dryland et al. J. Chem. Soc. Perkin I 1986 pp. 125-137.

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