The Awuah Laboratory is a multidisciplinary research group at the nexus of organic, inorganic chemistry and biology. We are focused on developing novel synthetic methods that give rise to chemical tools that interrogate complex biological processes such as the mitochondria in human health and small-molecule compounds as therapeutics for several disease indications. We are a highly energetic and collaborative group, poised to solve important problems in biomedicine, chemical biology, and catalysis. Our trainees gain extensive experience in chemical synthesis with a focus on transition metal elements, metalloids, and organic synthesis. Upon completion of their tenure, researchers become experts in various characterization methods including but not limited to multinuclear NMR, UV-vis, electrochemistry, functional biology & tissue culture, and mouse tumor models. The Awuah Group is equipped with standard tools for computational, chemical synthesis, mechanism-of-action studies through to animal studies as well as a variety of specialty equipment for handling reactive molecules. Our current activities involve four broad research facets:
Targeted Metallo-probe/drug Discovery
Clinically approved metal- and metalloid-containing drugs such as platinum, gold, boron, arsenic and antimony have revolutionized chemotherapy-based treatments of various diseases including cancer, rheumatoid arthritis, and antimicrobial infections. Platinum therapy (cisplatin, carboplatin, and oxaliplatin) remains the first line chemotherapy for testicular, bladder, lung, colon, and ovarian cancer types. The gold-containing drug, auranofin is used to treat patients with active and severe rheumatoid arthritis who have failed to respond to other medications. Arsenic trioxide (trisenox) is used in the treatment of leukemia, whereas the boron-containing drug, bortezomib (velcade) is used as targeted therapy for multiple myeloma and mantle cell lymphoma. Despite transformational outcomes of metallodrugs, unwanted toxicity and acquired resistance remain major therapeutic obstacles. The development of new metal-based drugs is at a snail pace due to lack of compound libraries for screening, unexplained cytotoxicity, poor pharmacokinetics, limited in vivo potency, and toxic side effects. Our research interest is focused on leveraging unique structural diversity of transition metal and metalloid complexes with streamlined functional and systems biology to identify efficacious drug leads. Of importance is to design and employ novel drug leads to exploit pathophysiological vulnerabilities in cancer, microbial infections, digestive and neurodegenerative diseases toward targeted metallodrugs. A major biological target of interest in this research space for our laboratory is the mitochondria.
Metal-mediated Ligand Affinity Chemistry
The gold subgroup together with the drug discovery subgroup are working to provide innovative solutions to target proteins without binding pockets via covalent trapping. Targeting proteins via chemical modification is a new powerful methodology to elucidate protein function. This has led to the identification of biological targets, antibody drug conjugates, and small-molecule covalent drugs. In the past two decades, bioorthogonal methods have advanced to include chemically selective reactions of fluorescent agents, drugs, or affinity tags with proteins carrying functionalized amino acids, and are now valuable strategies for selective protein labeling. Bioorthogonal methods, however, involve two steps: i) incorporation of the bioorthogonal handle (e.g. non-canonical amino acid, enzyme domain, peptide sequences) and ii) the binding of functional molecules such as drugs, affinity tags, and fluorophores. This two-step protocol often involve genetic manipulation, which make it impossible to chemically modify endogenous proteins in living systems. Thus, we propose the development of a transition metal-based chemical strategy that is ligand-directed to the endogenous protein of interest in a single step, which we refer to as metal-mediated ligand affinty chemistry (MLAC).
Small-molecule inhibitors of Protein-Protein Interaction (PPI)
Our group is interested in developing small-molecule inhibitors of non-enzymatic proteins or those that lack a defined binding site/pocket. The human genome contains approximately 20,000 protein coding genes, however, only about one fourth of gene products (~5,000) are considered druggable using current approaches.As such, over three quarters of the potential drug targets remain inaccessible, which severely limits the capability to develop effective pharmacological therapy for a wide variety of disease states. Most proteins exist in nature as multi-protein complexes or interact directly with other proteins via protein-protein interactions.There are ~650,000 protein-protein interactions in humans.Therefore, these protein-protein interactions represent an enormous possible target space for the development of drugs which is currently, at best, underutilized. Our drug discovery subgroup uses computer-aided drug design, medicinal chemistry, in vitro prioritization strategies to identify selective and potent hit compounds against targets, such as PD-L1, c-MYC, and ARID4B. These compounds can be used as chemical probes or therapeutics.
Catalysis & Synthetic Methods
Our group is interested in improving gold-catalyzed cross-coupling with an emphasis on 1) catalyst discovery without the use of external oxidants 2) functional group tolerance, 3) atom-economy & scalability, and 4) selectivity. The challenge of redox-neutral gold catalysis is largely because gold(I) is sluggish in undergoing oxidative addition due to its high redox potential. Gold-catalyzed cross-coupling methods that are redox-neutral is an attractive and burgeoning area of research with great promise. Pioneering work has stimulated the pursuit of oxidative addition at gold(I) centers. Gold(I) compounds with tricoordinate configuration was shown to be activated towards oxidative addition by aryl halides and pi systems. The use of hemilabile gold(I) catalysts efficiently promote cross-coupling reactions of electron-rich arenes with aryl iodides. Accumulating studies have led to the establishment of elementary organometallic transformations (oxidative addition, transmetallation, reductive elimination) by gold. The development of catalysts capable of direct arylation without external oxidants is an unmet need in gold-catalysis toward transformations such as biaryl synthesis. New catalysts developed in our lab suggest potential solutions that will contribute immensely to the field.