Modification of Poly(5,6-epoxy-l-norleucine) Gives Functional Polypeptides with Alternative Side-Chain Linkages.

The preparation and characterization of a new epoxide containing polypeptide, poly(5,6-epoxy-l-norleucine), via postpolymerization modification of poly(l-homoallylglycine) is described. Addition of thiols to the epoxide groups in poly(5,6-epoxy-l-norleucine) was studied as a means to prepare side-chain functional polypeptides. The solution properties of the derivatized polypeptides were studied in water and compared to similar thioether containing functional polypeptides prepared via different routes. Subtle differences in side-chain linkage chemistry were found to influence polypeptide solubility, chain conformation in solution, and thermoresponsive behavior. Poly(5,6-epoxy-l-norleucine) was found to be useful as a readily prepared intermediate that can be reacted with thiols to give a variety of functional polypeptides

Homoallylglycine residues are superior precursors to orthogonally modified thioether containing polypeptides.

Homoallylglycine N-carboxyanhydride, Hag NCA, monomers were synthesized and used to prepare polypeptides containing Hag segments with controllable lengths of up to 245 repeats. Poly(l-homoallylglycine), GHA, was found to adopt an α-helical conformation, which provided good solubility in organic solvents and allowed high yield functionalization of its alkene side-chains via radical promoted addition of thiols. The conformations of these derivatives were shown to be switchable between α-helical and disordered states in aqueous media using thioether alkylation or oxidation reactions. Incorporation of GHA segments into block copolymers with poly(l-methionine), M, segments provided a means to orthogonally modify thioether side-chains different ways in separate copolypeptide domains. This approach allows preparation of functional polypeptides containing discrete domains of oxidized and alkylated thioether containing residues, where chain conformation and functionality of each domain can be independently modified

Polypeptide gels incorporating the exotic functional aromatic amino acid 4-amino-L-phenylalanine

High-molecular-weight polypeptides with functional aromatic side chains, poly(4-amino-l-phenylalanine), were prepared by the metal-initiated polymerization of the Nα-carboxyanhydride of the corresponding amino acid, which is a microbial derivative of phenylalanine

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

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 derivativeswere 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

Homoallylglycine residues are superior precursors to orthogonally modified thioether containing polypeptides.

Homoallylglycine N-carboxyanhydride, Hag NCA, monomers were synthesized and used to prepare polypeptides containing Hag segments with controllable lengths of up to 245 repeats. Poly(l-homoallylglycine), GHA, was found to adopt an α-helical conformation, which provided good solubility in organic solvents and allowed high yield functionalization of its alkene side-chains via radical promoted addition of thiols. The conformations of these derivatives were shown to be switchable between α-helical and disordered states in aqueous media using thioether alkylation or oxidation reactions. Incorporation of GHA segments into block copolymers with poly(l-methionine), M, segments provided a means to orthogonally modify thioether side-chains different ways in separate copolypeptide domains. This approach allows preparation of functional polypeptides containing discrete domains of oxidized and alkylated thioether containing residues, where chain conformation and functionality of each domain can be independently modified

Modification of Poly(5,6-epoxy-l-norleucine) Gives Functional Polypeptides with Alternative Side-Chain Linkages.

The preparation and characterization of a new epoxide containing polypeptide, poly(5,6-epoxy-l-norleucine), via postpolymerization modification of poly(l-homoallylglycine) is described. Addition of thiols to the epoxide groups in poly(5,6-epoxy-l-norleucine) was studied as a means to prepare side-chain functional polypeptides. The solution properties of the derivatized polypeptides were studied in water and compared to similar thioether containing functional polypeptides prepared via different routes. Subtle differences in side-chain linkage chemistry were found to influence polypeptide solubility, chain conformation in solution, and thermoresponsive behavior. Poly(5,6-epoxy-l-norleucine) was found to be useful as a readily prepared intermediate that can be reacted with thiols to give a variety of functional polypeptides

Versatile N-Methylaminooxy-Functionalized Polypeptides for Preparation of Neoglycoconjugates.

The preparation and characterization of a new set of well-defined polypeptides containing N-methylaminooxy side-chain functionality is described. These functional groups enabled the direct coupling of polypeptides with a variety of unmodified reducing saccharides in water to give neoglycopolypeptides in high yields. The use of different polypeptide scaffolds resulted in neoglycoconjugates with tunable chain conformations, hydrophobicity, and charge. These new neoglycopolypeptides were also found to be stable in aqueous media at pH 7.4 and 37 °C for 1 week. The combination of straightforward synthesis using unmodified saccharides, high yields of saccharide conjugation, and conjugate stability makes these polypeptides attractive candidates for development of degradable glycoprotein mimics

Polypeptide gels incorporating the exotic functional aromatic amino acid 4-amino-L-phenylalanine

High-molecular-weight polypeptides with functional aromatic side chains, poly(4-amino-l-phenylalanine), were prepared by the metal-initiated polymerization of theNα-carboxyanhydride of the corresponding amino acid, which is a microbial derivative of phenylalanine