Functionalized Poly(methionine): Methods and Applications
- Author(s): Gharakhanian, Eric Gregory;
- Advisor(s): Deming, Timothy J;
- et al.
Polypeptide materials enjoy a wide breadth of realized and potential applications in the fields of biotechnology, medicine, tissue engineering and drug delivery. Key to enabling the progress of this field is developing and applying new synthetic methodologies that allow access to more complex materials easily and efficiently. As polypeptide materials are being used in evermore complex systems to tackle increasingly difficult problems, flexible rapid syntheses are required.
This dissertation will recount the development and application of new methodology for the functionalization of thioether residues in methionine (Met) containing polypeptides. A new method for the alkylation of Met residues by ring opening of epoxides under acidic protic conditions was developed, providing alkyl-methionine (MetR) sulfoniums. This method was amenable for introducing large functional groups such as glyco and oligoethylene glycol (OEG). The chemoselectivity of this transformation was investigated; selective thioether functionalization was found to be possible in the presence of nucleophilic residues such as lysine and cysteine. The sulfoniums were found to be stable under physiological conditions and in the presence of nucleophiles. The high stability of these epoxide adducts in comparison to other MetR derivatives was further explored. The course of the reaction of MetR with sulfur containing nucleophiles was found to be easily controlled by proper choice of substrate and conditions. For these and other sulfoniums, selective demethylation of certain MetR derivatives to functional R-HCys products could be achieved. This reaction was used to introduce a wide degree of structural diversity into Met containing polypeptides. These new methodologies were used to study the effect of certain molecular features on the lower critical solution temperature (LCST) of OEG-HCys derivatives. A library of OEG-HCys polypeptides was synthesized, allowing the effect of three different structural features on the LCST to be systematically analyzed. This allowed predictable tuning of the LCST of these materials by modification of sidechain structure and polypeptide conformation.