1. Departments of Pharmaceutics and Pharmaceutical Chemistry, and of Bioengineering, University of Utah, Salt Lake City, Utah, 84112, USA;2. Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, 84112, USA
Abstract:
A series of peptides of general primary structure (VSSLESK)n (n = 2, 3, 4, 5 and 6) were designed and synthesized by fluorenylmethyloxycarbonyl solid-phase synthesis using a convergent approach. Peptides containing 21, 28, 35 and 42 residues were modified with α-methoxy poly(ethylene glycol) (mPEG; mol. wt. 2000) by reaction of mPEG–succinimidyl carbonate with the α-amino group of the resin-attached protected peptides. The conformation and thermal stability of the peptides and of their AB block copolymers (A is the mPEG block, B the (VSSLESK)n block) in aqueous medium were investigated by circular dichroism, size-exclusion chromatography and by analytical ultracentrifugation. The helicity of peptides increased with increasing length in a cooperative manner. The peptides and mPEG–peptides with 35 and 42 amino acid residues (block copolymers) adopted a two-stranded α-helical coiled-coil conformation in aqueous solution. The presence of the polymer chain in the diblock hybrid copolymers had no disturbing effect with respect to the stability of the α-helical peptide part in these constructs. Moreover, the thermal stability of mPEG-modified 42-peptide was substantially higher than that of the native 42-peptide. Analytical ultracentrifugation data revealed that in phosphate-buffered saline solution (25–200 μM ) the block copolymer mPEG-block-(VSSLESK)6 ( PEG42 ) associated into stable intermolecular coiled-coil dimers.
Thermal melting profiles of peptides and mPEG–peptides at concentration 0.4 g · L−1 in PBS. Molar ellipticity at 222 nm versus temperature. Heating rate 0.5 °C · min−1.
