Peptide-Based Drug Design

240 Cudic and Stawikowski
of fully protected monomeric building blocks are described in the literature
(78,79), it will not be further described in this chapter. It is noteworthy that
coupling of monomeric units using this method is more difficult to perform in
comparison to using peptides due to secondary amine’s low reactivity if electronwithdrawing
groups are attached, and also due to the sterical hindrance around
this atom. Therefore, for these difficult couplings, reagents such as PyBroP,
PyBOP, or HATU are recommended.
Since the standard solid-phase peptide synthesis starts from the C-terminus
and finishes at the N-terminus, solid-phase peptoid and peptide synthesis could
be combined, giving peptide–peptoid hybrid polymers. Ostergaard and Holm
named such hybrids peptomers (82). This approach may also be used in
the conversion of biologically active peptide ligands, e.g., peptide hormones,
protease inhibitors, into an active peptomeric version by ensuring that the
essential amino acids comprising the lead motif are included in the synthesis
(77). Both peptoids and peptomers can be easily sequenced using modified
Edman degradation conditions (83).
This protocol was adopted from refs. (80) and (81).
1. Place the resin in dry reaction vessel.
2. Remove the Fmoc-protecting group (if necessary) by agitating the resin with 20%
piperidine in DMF (3 × 6min).
3. Wash the resin (3 min each) with 3 × 10 mL of DMF; and 3 × 10 mL of DCM.
4. Dissolve bromoacetic acid (10 eq, relative to resin loading) and DIC (11 eq) in
minimal amount of DMF. Add this solution to the resin.
5. Allow the resin to agitate at room temperature for 30 min.
6. Wash the resin (3 min each) with 3 × 10 mL of DMF.
7. Dissolve amine (25 eq) in DMSO, NMP, or DMF.
8. Allow the resin to agitate at room temperature for 2 h (see Note 16).
9. Wash the resin (3 min each) with 3 × 10 mL of DMF; and 3 × 10 mL of DCM.
10. Repeat these steps for each coupling cycle.
11. Cleave synthesized peptoid from the resin using TFA and appropriate scavengers
(see Note 12).
12. To the solution containing cleaved peptoid product, add cold diethyl ether and
collect the resulting precipitate by filtration.
13. Purify crude product by RP-HPLC.
4. Notes
1. Addition of NaBH4 causes strong evolution of H2. Use of a fume hood is strongly
recommended.
2. If alcoholic product does not precipitate, purify the product by extraction with
the appropriate organic solvent.