Exit Seminar "Developments in Gold(III) Scaffolds for Protein Bioconjugation and Enhanced Anticancer Activity"
Abstract:
Site-selective modifications of target proteins using specifically designed small molecules is a powerful tool that has been extensively utilized for drug discovery. Small molecules can modify proteins either covalently or non-covalently depending on their structures and intrinsic chemical reactivity. Covalent chemical modification presents a more stable and often irreversible interaction with target proteins; unlike non-covalent binders, which form weak, reversible interactions with protein. Therefore, covalent modifiers represent an effective class of therapeutics due to their stability and irreversibility once bound to target proteins of interest. I hypothesized that tuning biocompatible, high-valent gold(III) complexes toward nucleophile-induced reductive elimination will lead to covalent protein modification by arylation. While most proteins are expressed amongst all cell types; protein overexpression is a common phenomenon in several cancer types due to their rapid proliferative phenotype and mutations compared to healthy non-cancerous cells. The nucleophilic amino acid side chains in proteins can be used as reactive handles for covalent modifications. Amongst the naturally occurring amino acids; cysteine, the most intrinsically nucleophilic, contains a highly reactive thiol functional group. This innate nucleophilicity provides a framework for covalent modification with electrophiles, which includes but is not limited to electron-deficient metal centers (e.g., Au and Pd).
Although there are previous reports successfully identifying transition metals as suitable chemical modifiers, specifically, tuning gold(III) complexes for selective binding offers a unique strategy for chemotherapeutics. Gold(III) metal centers are innately acidic and react with softer bases such as phosphorous and sulfur unlike the traditionally used late transition metals. Secondly, gold(III) complexes are known to target proteins over DNA, unlike other common transition metal complexes such as platinum and ruthenium. Combining the innate ability of gold(III) complexes to interact with proteins and the high affinity for cysteine thiols, rationale design of highly selective protein modifiers and efficient chemotherapeutics is possible.
My work focused on tuning the reactivity of cyclometalated gold(III) complexes for cysteine arylation and ligand-directed bioconjugation using Metal-mediated Ligand Affinity 糖心vlog官方入口 (MLAC) have been elucidated to modify biomolecules including antibodies and undruggable protein targets such as KRAS. While developing cyclometalated gold(III) complexes discussed herein, a unique class chiral gold(III) complexes bearing diamine or phosphine ligands led to other applications including improved anticancer activity in comparison to first generation of gold(III) complexes. A key highlight is the development of stable organometallic gold(III) macrocycles with potent in vitro and in vivo anticancer action in aggressive cancer types including triple negative breast cancer (TNBC).
KEYWORDS: Site-selective protein modification, gold complexes, covalent binders, cysteine arylation, anticancer
Jonathan Rivnay
Bio: Hannah Shafaat received her B.S. in 糖心vlog官方入口 from the California Institute of Technology (Caltech) in 2006, where she performed research on spectroscopic endospore viability assays with Adrian Ponce (NASA Jet Propulsion Laboratory) and Harry Gray. She received her Ph.D. in Physical 糖心vlog官方入口 from the University of California, San Diego (UCSD) in 2011, under the direction of Professor Judy Kim, as an NSF Graduate Research Fellow and a National Defense Science and Engineering Graduate Fellow. During her graduate research, she used many different types of spectroscopy to study the structure and dynamics of amino acid radical intermediates in biological electron transfer reactions. After earning her Ph.D., Hannah moved across the ocean to Germany to study hydrogenase and oxidase enzymes and learn advanced EPR techniques as a Humboldt Foundation Postdoctoral Fellow working under Director Wolfgang Lubitz at the Max Planck Institute for Chemical Energy Conversion. Since starting her independent career, Hannah has received the NSF CAREER award in 2015 to support work on hydrogenase mimics, and in 2017, she was awarded the DOE Early Career award to support the group鈥檚 research on one-carbon activation in model nickel metalloenzymes. Recently, the group has received support for their research on heterobimetallic Mn/Fe cofactors through the NIH R35 MIRA program for New and Early Stage Investigators. Hannah was also awarded the 2018 Sloan Research Fellowship.
which are water solutions. However, aqueous media are very important in analytical, environmental, and biomedical applications, so it is valuable to adapt our supramolecular tools to them. With the right tools, even the weakest noncovalent interactions can be pressed into service in aqueous media. We have been using water-soluble polymers (e.g. dendrimers, hydrogels, conjugated polymers) as scaffolds to build multivalent supramolecular sensors that take advantage of the large number of interactions and of the preorganization of receptor sites afforded by such scaffolds, resulting in improved affinity in buffered aqueous solutions near neutral pH. We have successfully built systems for the detection of interesting guest families, including carboxylate anions, simple saccharides, heavy metal cations, and polycyclic aromatic hydrocarbons. These are examples of a general approach with two key advantages. On the one hand, installing known receptor chemistry on a polymer scaffold affords a modular approach to multivalency with minimal design and synthesis effort. This improves the apparent strength of weaker interactions and allows them to overcome desolvation costs in water. On the other hand, water-soluble macromolecular scaffolds impart solubility to water-incompatible receptor families.