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Open Access Publications from the University of California

Modification of poly(L-Homoallylglycine) for the Synthesis of Functional Polypeptides

  • Author(s): Perlin, Pesach
  • Advisor(s): Deming, Timothy J
  • et al.

Synthetic polypeptides have demonstrated great potential for a variety of biomaterial applications due to their ability to self-assemble into ordered structures. The ability to design polypeptides with a variety of functionalities is necessary for tailoring the solubility, conformational properties, and environmental responses of polypeptide-based materials. Post polymerization modification of reactive residues has emerged as a desirable method for the design of functional polypeptides due to straightforward monomer synthesis and purification and the potential to synthesize a variety of functional polypeptides from a single reactive polypeptide precursor. This dissertation describes the development and subsequent modification of poly(L-homoallylglycine), a soluble, α-helical alkene bearing polypeptide.

L-Homoallylglycine N-carboxyanhydride monomers were synthesized and used to prepare poly(L-homoallylglycine) polypeptides with controllable lengths of up to 245 residues. These polypeptides were modified under mild conditions via UV initiated thiol-ene chemistry to give a variety of α-helical water soluble thioether containing polypeptides. These derivatives

were able to undergo a conformational change from α-helix to random coil upon thioether oxidation or alkylation. Incorporation of L-homoallylglycine residues into block copolypeptides with L-methionine residues allowed for the synthesis of block copolypeptides with separate ordered segments of sulfoxide residues and sulfonium residues.

The thiol-ene reactivity of poly(L-homoallylglycine) was then utilized to synthesize polypeptides containing N-methylaminooxy functionality. The solubility, conformation, and reactivity of these poly(L-Homoallylglycine) derived polypeptides was compared to more hydrophilic N-methylaminooxy polypeptides synthesized via a functional monomer approach. The unique reactivity of N-methylaminooxy groups with non-protected reducing sugars facilitated the straightforward synthesis of glycopolypeptides which possessed good aqueous solubility and were stable at pH 7.4 for one week. This post polymerization modification technique shows promise as a potential strategy for the synthesis of proteoglycan mimics.

The thiol-ene chemistry of poly(L-homoallylglycine) was proven to be highly versatile, but the resulting thiol-ene conjugates often have limited aqueous solubility due to their long hydrophobic side chains. Therefore, poly(L-homoallylglycine) was oxidized to an epoxide bearing polypeptide, poly(5,6-epoxy-L-norleucine) and modified with thiols under basic conditions to synthesize a variety of β-hydroxy thioether containing polypeptides with considerably higher aqueous solubility than previously synthesized thiol-ene conjugates. Diethylene glycol thiol modified poly(5,6-epoxy-L-norleucine) derivatives displayed lower critical solution temperature properties in water that could be modulated by varying polypeptide concentration, polypeptide composition, and could be switched off through oxidation of their thioether groups.

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