In this project funded by the Macromolecular, Supramolecular and Nanochemistry Program of the Chemistry Division, Timothy Deming of the University of California at Los Angeles will develop strategies for the addition of sugar functionality to peptide based polymers. Sugar functionalized amino acid monomers will be prepared with different chemical linkages for sugar attachment, and methods for efficient polymerization of these monomers into a variety of polypeptide architectures will be developed. The different sugars and linkages employed will be used to control the presentation of biomolecular functionality and to influence the macromolecule's interactions with other polymers and biomolecules. This project will be performed in collaboration with Henning Menzel at the Technical University of Braunschweig, Germany, Helmut Schlaad of the Max-Planck-Institute for Colloids and Interfaces, Germany, Sebastien Lecommandoux of the University of Bordeaux, France, and Andreas Heise of the Dublin City University, Ireland. Together, these groups will combine their separate areas of expertise to prepare and study sugar functionalized polypeptides of unprecedented order and hierarchical complexity. The broader impacts involve the development of infrastructure for research and education through the creation of new multilateral international collaborations, the promotion of this growing field via organization of an international symposium on sugar-functionalized polymers, and the promotion of teaching, training and learning of graduate students through this research project and an international exchange of ideas and expertise.
This work will expand the repertoire of chemistry that can be used to create new polymers that mimic natural biomaterials. The results of these studies could have many important long term impacts on a variety of applications and industries in which biomimetic polymers are important, including drug delivery, regenerative medicine, and medical diagnostics.
The goal of this project is to develop new synthetic methodologies for the synthesis of glycopolypeptides and multifunctional polypeptides. Intellectual Merit of the Accomplishments: The synthesis of glycopolypeptides has attracted interest from many research groups worldwide in recent years. We first reported the preparation of fully glycosylated, high molar mass synthetic polypeptides, which are water soluble and mimic the structures of naturally occurring glycoproteins. A key feature of these glycopolymers is that their chain conformations are readily controlled, either by choice of peptide backbone or by selective oxidation of side-chain functional groups, such that fully α-helical or fully disordered chains can be obtained. We next incorporated these glycopolypeptides as hydrophilic segments in amphiphilic diblock copolypeptides to study their aqueous self-assembly and evaluate the properties of the resulting nanostructures. While much is known about how different chain conformations of hydrophobic polypeptide segments influence nanoscale morphology, little is known about the corresponding role played by hydrophilic polypeptide conformations in self assembly. This has been difficult to study since hydrophilic polypeptide segments presenting similar functionality but differing only in conformation are rare. In this project, we have found that block copolypeptides containing galactosylated hydrophilic segments of either α-helical or disordered conformation give different assembly morphologies, where the disordered glycopolypeptide segments favor vesicle formation and present sugar residues that can bind to biological targets . As an alternative process for preparation of functional and glycopolypeptides, we developed a new "click" type reaction for polypeptides that utilizes the unique reactivity of the thioether group found in the natural amino acid methionine. We have found that methionine can undergo chemoselective, broad scope, highly efficient alkylation reactions in homo- and copolypeptides yielding stable sulfonium derivatives. These "methionine click" functionalizations are compatible with deprotection of other functional groups, use an inexpensive, natural amino acid that is readily polymerized and requires no side-chain modification or protecting groups, and allow the introduction of a diverse range of functionality and reactive groups onto polypeptides. In comparison to other methods for installation of functional and click reactive groups onto polypeptides, the starting material methionine is substantially less expensive than the side chain modified or unnatural amino acids typically employed, and poly(Met) is readily prepared with controlled and high molecular weights, which makes these "methionine click" reactions attractive for large-scale use. Facile incorporation of other click-reactive functional groups (e.g. alkyne, azide, or alkene) by methionine alkylation also allows for further chemoselective modification of polypeptides. Recently, we developed reagents to allow chemoselective tagging of methionine residues in peptides and polypeptides, subsequent bioorthogonal functionalization of the tags, and cleavage of the tags when desired. This methodology is potentially useful for triggered release of therapeutic peptides, or release of tagged protein digests from affinity columns in proteomic analyses. Broader Impacts of the Accomplishments: One of the goals of this project was to provide young researchers (graduate students and postdocs) with the opportunity to work in an international collaborative environment as part of a four country IUPAC research team. One graduate student, Jessica Kramer, participated in the international meetings of our IUPAC glycopolypeptide group: the first held in Dublin, Ireland on May 26-27, 2011, and the most recent in Bordeaux, France on June 12-13, 2012. Here, she was able to present her results and discuss research opportunities with our collaborators from Ireland, Germany and France. Several new ideas have come out of these discussions, as well as visits of students to collaborator labs. Dr. Colin Bonduelle from our collaborator in France, and Kai Krannig from a German collaborator, both worked my UCLA lab during the grant period. Prof. Deming also developed two new courses in the Bioengineering Department at UCLA during this period: BE 205 Bioconjugate chemistry for engineers and BE 207 Biopolymer Chemistry, which both incorporated concepts from this research. Overall, we have trained 3 Ph.D. students and 1 MS student in this project. Some of these students came from underrepresented groups (e.g. black female). To disseminate her findings, Jessica Kramer has given many presentations on this project, including a talk in the Excellence in Graduate Research Symposium of the POLY and PMSE divisions at the ACS National Meeting in San Diego in March 2012, as well as at the 2012 Organic Graduate Research Symposium at UCLA. Recently, Jessica also participated in a NSF sponsored Future Faculty Workshop at UC Santa Barbara, and took advantage of supplemental funding to present a poster at the Polymer Chemistry Gordon Research Conference.We have also published 5 research papers and 1 review article to disseminate our findings.
