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 2022-03-23 19:56:53

Novel Concepts for the Design and Manufacture of Solid Supports for Synthesis of Peptides

Abstract Two novel concepts for the design and manufacture of polymer supports for solid phase synthesis of peptides are described. The first concept involves the encapsulation of polymers within the hole of short pieces of capillary tubing often referred to as seed beads. This provides a rigid exo-skeleton for the support of soft polymer gel and other mechanically fragile polymer based matrices. The rigidity of the support provides a polymeric media that is particularly suited to continuous fiow based peptide synthesis. The second concept complements this by providing an inexpensive approach to the preparation of spherical polymer particles by coating commercially available impervious hollow glass microspheres with polymer. The added advantage of this approach lies in the buoyancy of the resultant polymer particles, which facilitates handling on a large scale

Keywords Solid supports. Peptide synthesis .Polymer particles . Seed beads. Continuous flow . Stirred reactor . Polydimethylacrylamide . Soft gels . Microporous polymers

Introduction

Polymeric particles used in the solid phase synthesis of peptides are typically be made by a dispersion or emulsion polymerization process in which a solution of monomers is dispersed in an immiscible solvent (continuous phase) prior to initiation of the polymerization. The polymer particles formed are typically then filtered, washed and classified to isolate the required particle size distribution. These processes are disadvantageous in some respects which includes monomer loss to the continuous phase, generation of a range of particle sizes and the undesirable generation of fine particles during the polymerization.

The subsequent laborious particle size classi- fication, for example sieving and air classification adds to the expense of the current manufacturing processes. In addition to undesirable costs of manufacture and wastage during preparation certain disadvantages may arise with the physical properties of the known polymeric particles. Microporous polymeric particles are generally soft and difficult to handle in both stirred tanks and column based reactors. In addition, the soft particles may be compressed undesirably and cause fouling, for example, during filtration often leading to compressive intrusion into the sinter or mesh being used at the bottom of the reactor. Rigid macroporous and macroreticular particles are more suited to high fiow rates in packed column beds. However, due to the rigid nature the particles may be fragile and fragment under physical stress.

Two technologies are described in this paper which provides alternative approaches to the current polymer particle design applied to continuous fiow based peptide synthesis and batch-wise operations in stirred tanks. In the first technology, described in patent WO2008/012064, we describe a polymer-impregnated bead wherein the bead has a hole in it

and the polymer is disposed in the hole. This technology involves the encapsulation of polymers within the hole of short pieces of capillary tubing often referred to as seed beads. These polymer filled seed beads are readily packed into columns and operate efficiently under continuous fiow conditions. In the second, patented technology we have now found

that the problems described above and other problems associated with traditional polymer particles may be ameliorated by providing a particulate support comprising a preformed hollow microsphere having a polymer coated on its surface. The hollow microsphere centre not only provides a uniformly sized particle but also provides a particulate

support of a low density resulting in buoyancy in a liquid phase.

Materials and Methods

Concept 1

The glass seed beads used to encapsulate polymer matrices were purchased from Miyuki Beads Co Ltd, The glass seed beads used to encapsulate polymer matrices were purchased from Miyuki Beads Co Ltd, Zip-Code 720-0001, 749 Kamiiwanari, Miyuki-Cho, Fukuyama-Shi, Hiroshima-Pref., Japan. The seed beads used here were 0.6 mm length with a diameter of 0.5 mm and hole diameter of 0.4 mm. The beads were etched, surface coated to allow covalent binding of the polymer and filled with the traditional polydimethylacrylamide based polymer described by Arshady et al. (1981) and also in patent WO2008/012064.

Concept 2

Hollow glass microspheres supplied by Potters Beads Europe were etched, surface functionalized to allow covalent binding of the polymer and coated with the traditional polydimethylacrylamide based polymer described

by Arshady et al. (1981) and also in patent application GB0916281.9.

Peptide Synthesis

The immobilized polymers described in Concepts 1 and 2 were used to prepare Leu-enkephalin amide and ACP (65–74) amide. Standard Fmoc/TBTU based protocols described by Atherton and Wellings in (2001) Houben- Weyl, Methods of Organic Chemistry were used for peptide synthesis. Analytical HPLC was used to compare the crude products in relation to those prepared on traditional polydimethylacrylamide supplied by Polymer Laboratories, Church Stretton, Shropshire UK and polystyrene supplied by Bachem AG, Switzerland

Results and Discussion

The concepts described in this paper are complementary yet inextricably linked in that the key starting constructs for each technology are commercially available at very large scale with an extremely low cost.

The new technology described for continuous fiow based synthesis of peptides allows for the immobilization of extremely soft polymer gels that could not otherwise be used for peptide synthesis. Hydrophilic, highly solvated polymers with low levels of cross linking will facilitate the

synthesis

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