Base Resins for Peptide Synthesis

The Novabiochem® product line has one of the most extensive ranges of polymer-supports for solid phase peptide synthesis. They range from high-loaded, low swelling for the large scale production of relatively short peptides to high-swelling, low-loaded for the synthesis of long or difficult sequences.

For peptide synthesis, the use of small particle-sized resins of low crosslinking is favored. Such resins allow for rapid diffusion of reagents inside the beads and their swelling enables them to better accommodate the bulk of the growing peptide chain. The most commonly used resins are based on 1% divinylbenzene-crosslinked polystyrene. These are relatively low-cost, easy-to-handle, and have high substitution. They are normally employed for batch-wise synthesis, with gas-bubbling, shaking, paddle stirring, or vessel inversion used for mixing. However, they can also be used in continuous flow synthesis, provided a low flow-rate is used or the resin is co-packed with glass beads, although for this application NovaSyn® TG, NovaGel™, NovaPEG, or PEGA composite resins are preferred. Here, the solvation of the PEG confers pressure stability on the polymer, making them suitable for use in pumped-flow systems.


Table 1. Properties of base resins

  Composition Bead size (mm)/mesh Loading DMF H20 DCM Application Comments
Polystyrene Styrene cross-linked with divinylbenzene 75 - 150/
100 - 200
0.5 -1.0 3 0 7 Routine and large scale synthesis Most cost-effective but can fail on synthesis of difficult or long sequences
NovaSyn® TG PEG grafted on polystyrene 90/160 0.2 – 0.3 5 4 5 Research scale medium to long peptides Pressure resistant, thus ideal for continuous flow
NovaSyn® TGR PEG grafted on polystyrene 90/160 0.2 – 0.3 5 4 5 Research scale medium to long peptides Special formulation of NovaSyn TG resin which gives even better results for long peptides . Works particularly well under microwave heating
PEGA Polyacrylamide-PEG copolymer 150 - 300/
100 - 300
0.2 – 0.4 11 16 13 On-bead enzyme assays Internal bead space accessible to many proteins
NovaGel™ (Champion) PEG grafted on polystyrene 75 - 150/
100 - 200
0.6 – 0.8 7 n/d n/d Synthesis of medium length peptides High-loading and high PEG content make it ideal for preparing medium-length peptides in quantity.
Polyethene cross-linked with PEG 75 - 100/
100 - 200
0.4 – 0.6 8 11 13 Long or difficult peptides Quality of long peptides excellent but yields often low


NovaSyn® TG resins

NovaSyn® TG and NovaSyn® TGR resins1 are based on a composite of low cross-linked hydroxyethylpolystyrene and polyethylene glycol, which has been terminally functionalized. NovaSyn® TG resin is available as 90 µm and 130 µm beads. The smaller bead size resin is generally preferred for peptide synthesis and peptide libraries; 1 g contains almost a sufficient number of beads to represent a pentameric peptide library. The higher capacity of the large beads make the 130 µm resin ideal for the production of non-peptidic libraries.

These resins are suitable for both continuous flow and batch peptide synthesis. The NovaSyn® TGR resins have been specifically designed for the synthesis of long and challenging sequences. They have excellent physical stability in flow systems, are resistant to abrasion and mechanical pressure, and offer improved chemical efficiency. High flow rates have even been reported to increase the acylation and deprotection rates of NovaSyn® TG resins1b. NovaSyn®TG resins are also recommended for use with the one-bead-one-compound approach to chemical libraries. The beads have a narrow size distribution and swell in water, facilitating biological assays in aqueous systems. The resins swell in a wide range of solvents from toluene to water, and the environment provided by the PEG is thought to closely resemble that found in THF.

The PEG is anchored in NovaSyn®TG resins to the polystyrene backbone via an acid insensitive ethylphenyl ether. PEG leakage that many report as being associated with the use of these resins is not due to any inherent acid instability, but arises through formation of PEG peroxides by the actions of oxygen and light during long-term storage. This degradation is an intrinsic property of all PEG resins. Unfavorable comparisons made between NovaSyn®TG and other similar PEG-based supports almost certainly reflect differences in age and storage histories of the samples tested and not any fundamental differences in chemical stability.

Structure of NovaSyn® TG resin

Figure 1. Structure of NovaSyn® TG resin.

NovaGel™ resins

NovaGel™, also know as Champion resin, is a type of PEG-PS resin that has been designed to meet the requirements of chemists for resins of high substitution with broad solvent compatibility. It is prepared from a special high-swelling version of aminomethylated resin by partial derivatization with methyl-PEG2000-p-nitro-phenylcarbonate2-3. This produces a resin containing approximately 48% PEG, with a substitution of 0.7 mmole/g, which is almost twice that of conventional PEG-PS supports. It swells in solvents of such widely different polarities as THF, DMF, acetonitrile and methanol, making it an excellent support for both peptide and organic synthesis.

The urethane linkage between the PEG and the base resin is stable to piperidine and TFA, ensuring minimal loss of PEG chains during synthesis. However, if leaching of PEG does occur, this does not result in loss of substitution, as can be the case with other PEG-PS-based resins, because the linker is not attached to the end of the PEG chains.

Structure of NovaGel™ resin

Figure 2. Structure of NovaGel™ resin

PEGA resins

PEGA resins are hydrophilic polymers that were originally developed for batch and continuous flow peptide synthesis4 but which are also used in SPOS. They consist of 2-acrylamidoprop-1-yl-(2-aminoprop-1-yl) polyethylene glycol800 and dimethylacylamide cross-linked with bis 2-acrylamidoprop-1-yl polyethylene glycol800. These supports swell extensively in a wide range of solvents, including water, DMF, DCM, THF and MeOH, and are freely permeable to macromolecules up to 35kD, making them ideally suited for the preparation of peptide libraries, affinity purification, and on-resin enzyme assays. These properties have been exploited in the on-resin enzymatic synthesis of glycopeptides [5]; for determining the inhibitors of subtilisin Carlsberg6, Cruzipain7, cysteine proteases8, and matrix metalloproteinases9; and in studies on protein disulfide isomerases, using fluorescence-quenched libraries10.

Smith & Bradley11 compared solution and solid phase polyamine libraries in an assay against trypanathione reductase. The library on PEGA resin performed as well as that in solution, whilst the library on TG resin failed to work.

Structure of PEGA resin

Figure 3. Structure of PEGA resin

NovaPEG resins

NovaPEG resins are identical to ChemMatrix resins and are excellent solid supports for solid phase peptide and organic synthesis12. Unlike other PEG-based polymer supports such as NovaSyn® TG and PEGA resins, which contain either polystyrene or polyacrylamide backbones, NovaPEG resin contains only PEG units. This unique composition confers excellent swelling and mechanical properties on the polymer. The resin beads have similar swelling properties to PEGA resins but unlike PEGA resins are free flowing beads in the dry state, making them much easier to handle. Furthermore, in contrast to polystyrene and other commonly used supports, NovaPEG resin appears not to suffer from osmotic shock when solvent is exchanged from hydrophobic to hydrophilic solvents. NovaPEG resin also has excellent chemical stability, particularly towards strong acids and bases.

Structure of NovaPEG resin

Figure 4. Structure of NovaPEG resin.

The amphiphilic nature of this resin makes it an excellent support for the synthesis of difficult, aggregated peptides and of long peptides and small proteins. In a reported synthesis of Bacuma12, a 38-residue potential synthetic vaccine, the use of polystyrene-based resin gave an extremely heterogeneous product, whereas NovaPEG Rink Amide resin afforded the target in excellent purity and yield. More remarkable is the result obtained from the synthesis of β-amyloid (1-42)12. This sequence is notoriously difficult to prepare owing to its propensity to aggregate. Numerous strategies have been advocated for its synthesis, including the use of DBU, Hmb-dipeptides, and O-N intramolecular acyl migration. Using NovaPEG resin, this extremely problematic peptide was obtained in a crude purity of 91% using standard Fmoc SPPS methods. NovaPEG resin also gave a spectacular result in the synthesis of HIV-protease, affording an almost homogeneous product after 78 amino acid additions13.

Remarkable synergies have been observed when they are used in combination with pseudoproline dipeptides. For example, the syntheses of the chemokines Rantes14 and CCL4-L115 could only be achieved by employing both NovaPEG resins and pseudoproline dipeptides.



  1. a) W. Rapp et al. in “Peptides 1988, Proc. 20st European Peptide Symposium”, G. Jung & E. Bayer (Eds.), Walter de Gruyter, Berlin, 1989, pp. 199; b) W. Rapp, et al. in “Innovation and Perspectives in Solid Phase Synthesis”, R.Epton (Ed.), SPCC (UK) Ltd, Birmingham, 1990, pp. 205; c) L. Zhang et al. in “Peptides 1990, Proc. 21st European Peptide Symposium”, E. Giralt & D. Andreu (Eds), ESCOM, Leiden, 1990, pp. 196; d) E. Bayer (1991) Angew. Chem. Int. Ed. Engl., 30, 113; e) E. Bayer et al. in “Peptides Structure and Function”, V.J. Hubry & D.M. Rich (Eds.), Pierce Chemical Company, Rockford, 1983, pp. 87; f) W. Rapp and E. Bayer in “Polyethyleneglycol chemistry, Biochemical and Biomedical Applications”, J.Milton-Harris (Ed.), Plenum Press, 1992, pp. 325; g) W. Rapp, et al. in “Peptides 1994, Proc. 23rd European Peptide Symposium”, H. Maia (Ed.), ESCOM, Leiden, 1995, pp. 87.
  2. J. H. Adams, et al. (1998) J. Org. Chem., 63, 3706.
  3. D. Hudson, et al. (1999) in "Peptides 1998: Proceedings of the 25th European Peptide Symposium", S. Bajusz & F. Hudecz, Akadémiai Kiadó, Budapest, pp. 40.
  4. M. Meldal (1992) Tetrahedron Lett., 33, 3077.
  5. M. Meldal et al. (1994) J. Chem. Soc., Chem. Commun., 1849.
  6. M. Meldal et al. (1994) Proc. Natl. Acad. Sci. USA, 91, 3314.
  7. M. Meldal, et al. (1998) J. Peptide Sci., 4, 83.
  8. P. M. St. Hilaire, et al. (1999) J. Comb. Chem., 1, 509.
  9. J. Buchardt, et al. (2000) J. Comb. Chem., 2, 624.
  10. J. C. Spetzler, et al. (1998) J. Peptide Sci., 4, 128.
  11. H. K. Smith & M. Bradley (1999) J. Comb. Chem., 1, 326.
  12. F. Garcia-Martin, et al. (2006) J. Comb. Chem., 8, 213.
  13. S. Frutos, et al. (2007) Int.  J. Pept. Res. Ther., 13,  221.
  14. F. Garcia-Martin, et al. (2006) Biopolymers, 84, 566.
  15. B. G. de la Torre, et al. (2007) Int. J. Pept. Res. Ther., 13, 265.


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