1. Carbene Cascade Annulations (Organic/Inorganic and Organometallic Chemistry)
The goal of this research program is to utilize carbene initiated cascade reactions for the efficient scalable synthesis of underexploited scaffolds to explore uncharted chemical space in drug discovery. This chemistry is inspired from enzymatic cascades found in Mother Nature, where multiple transformations happen simultaneously in a single reaction. The objective of this project is to understand the reactivity of metal carbenes and their use in cascade reactions for the rapid assembly of diverse scaffolds of spirocycles, medium-sized rings and terpene furanolactones for the identification of new drug leads. The central hypothesis focuses on diazo-derived metal-carbenes that offer sequential reactions with a nucleophile and an electrophile, and ideal for cascade reactions, which are known to build complexity with high efficiency, selectivity, and atom economy.
2. Development of Non-Addictive Painkillers (Organic Synthesis/Drug Discovery)
Morphine, a mu-opioid receptor (μOR) agonist, is clinically preferred in pain management. However, prolonged morphine use is associated with side effects such as tolerance development, abuse liability, respiratory depression, and itching. Studies suggest that selective kappa-opioid receptor (kOR) agonists biased towards G-protein signaling over β-arrestin recruitment could lead to novel therapeutics for treating intractable itch and pain with reduced side effects. Thus, a key gap and critical need for effective pain management is the development of selective kappa-opioid analgesics with reduced side effects. Collybolide, a natural product isolated from the mushroom Collybia Maculata has exhibited potent analgesics properties without the side effects seen in well-known analgesics such as morphine, due to its selectivity for the kappa-opioid receptor. This project will focus on the synthesis and evaluation of collybolide analogues. This work will lead to a better understanding of the kappa-opioid receptor pharmacology to develop potential therapeutics for the treatment of pain with reduced addiction hazards.
3. Pro-Apoptotic Bax/Bak Inhibitors as Neuroprotective Agents (Structural Biology/Drug Discovery)
Pro-apoptotic Bax/Bak proteins are key regulators of the intrinsic apoptosis pathway. The oligomerization of these proteins within the mitochondrial outer membrane is directly responsible for the pore formation in membrane, which causes cell death. Therapeutic potential of anti-apoptotic Bcl-2 inhibitors as anticancer agents has been extensively studied, while there are no potent and selective inhibitors to pro-apoptotic Bax/Bak, which could lead to the development of neuroprotective agents. Therefore, the goal of this project is to develop potent and selective small-molecule inhibitors to pro-apoptotic Bax/Bak proteins. Our preliminary docking calculations and biological evaluation suggest that ABT-199 and ABT-263, two anti-tumor drugs, bind weakly to Bax proteins. Building upon these preliminary findings, we will design a library of ABT-199/263 analogues, which will be assessed using fluorescence, crosslinking, and pore-forming assays in vitro. The identified potent and selective Bax inhibitors will be evaluated in cells for their anti-apoptotic activity. Findings from these studies will facilitate both basic and applied apoptosis research, and provide a platform for the development of neuro/cardio-protective agents.
4. Lipids-Based Carriers in Drug Delivery (Chemical Biology/Drug Discovery)
RNA-interference (RNAi) agents such as small-interfering RNA (siRNA) and micro-RNA (miRNA) have strong potential as therapeutic agents for the treatment of a broad range of diseases such as malignancies, infections, autoimmune diseases and neurological diseases that are associated with undesirable gene expression. For systemic administration of these poorly permeable and easily degradable macromolecules, a safe and efficient delivery platform is highly desirable. Although several siRNA delivery materials have been developed with varying levels of success, efficient, selective, and safe delivery of siRNA is still a key challenge to the broad application of siRNA therapeutics in humans. To overcome this challenge, the goal of this research project is to develop lipopeptide-based carriers for siRNA delivery.