Chemo- and Regio- Selective Lysine Modification on the Surface of Native Proteins: Synthetic Methods for the Improvement of Cancer Therapeutics - Unmodified, from original application. Awarded under Grant 1F32GM131592-01A1
PROJECT SUMMARY/ABSTRACT
Protein modification has a variety of use cases, from cellular trafficking, targeted drug delivery, to imaging
biomarkers. For a medicinal chemist, a single small molecule scaffold can set the stage for a nearly limitless
number of controlled modifications to obtain an equally boundless set of well-defined derivatives for relevance
in the context of pharmaceuticals and related industries. However, while the chemical biologist can imagine an
infinite set of derivatives from a single protein scaffold, the tools available by which they may construct these
bioconjugates is severely bounded therefore limiting their ability to test biological hypotheses. Moreover, the
technology to enable large biomolecule coupling with stable linkages in stoichiometric quantities remains a
formidable challenge and any such technology is projected to have a significant impact in the field. The
preliminary results I have obtained not only enables robust, large protein-protein couplings at nanomolar
concentrations, but more generally serves as a platform for rapid biomolecule diversification under biologically
relevant conditions in the presence of diverse, unprotected functional groups.
By using chemoselective palladium-thiol chemistry for chemoselective modification of low abundant
cysteine residues, this proposal aims to expand the synthetic toolbox and chemical space available to chemical
biologists. This is accomplished by the development of organometallic palladium reagents for the preparation
stable, isolable, electrophilic organometallic palladium proteins for subsequent use in thiol couplings (Aim 1). To
further demonstrate the utility of these organometallic palladium proteins, Aim 2 of this proposal will take
advantage of this technology for the development of novel antibody-protein conjugates, an underexplored
avenue of research due to the lack of technology to prepare these constructs. Thus, this proposal aims to expand
the synthetic toolbox available for the chemical biologist to create a diversity of well-defined conjugates with the
developed palladium reagents. Mindful of their practical use, reagents will be readily prepared, robust, and bench
stable with protocols that can be easily implemented. With the goal of obtaining an academic job at a major
university conducting interdisciplinary research, my training here at MIT will allow me to gain needed experience
in chemical biology to complement my skills as a synthetic organic chemist. This will continue to entail hands-on
research experience. In addition, I will have ample experience in writing, both in the context of proposal writing
and manuscript preparation, mentoring, where I will continue to work with graduate and undergraduate students
to hone this skill, and oral presentation skills by attending various conferences and guest lecturing courses. At
MIT, I can continue to draw from the wealth of expertise in organometallic transformations from my colleagues
in the Buchwald lab as well as that of chemical biology in the Pentelute lab making this the ideal environment for
my post-doctoral training.
