"The progress of science requires the growth of understanding in both directions, downward from the whole to the parts and upward from the parts to the whole."
Freeman Dyson, The Scientist as Rebel
Naturally occurring catalysis for bond formation (via enzymes) is highly proficient (fast rate coupled to high enantio-selectivity), environmentally benign, self-regenerative, and exquisitely regulated. No designed catalytic systems can claim all of these four hallmarks of “ideal” catalysis. We currently address the proficiency issue by pioneering trifunctional organocatalysis in model proton-transfer reactions (PTRs), in which mild catalytic motifs cooperate, on a chiral backbone, for asymmetric carbon-carbon bond formation that is fundamental in both designed and living systems. Interesting reaction networks can also be built on proton-transfer sensitive transformations for understanding propagative properties that can be fueled by chemical energy. This can lead to novel approaches in chemcially evolving catalytic systems using carbon-based building blocks with a wide range of applications in sustainability science.
Enzymes are major drug targets, and their conformational flexibility is essential for finding isozyme-specific bioactive or drug leads. Protein flexibility however is difficult to predict thus presenting considerable challenges for rational drug discovery. We currently use natural products as leads for generating new conformation-based chemical diversity around existing functional epitopes to target new protein conformations for drug discovery by a combined experimental and computational approach that guides the iterative design/discovery cycle. New small molecule ligands capable of recognising protein conformational sensitivity will help glean insight into underutilized and targetable biological space for further exploration. This could lead to new drug design avenues in order to achieve the level of specificity required for developing efficacious medicines with minimal side effects.
Cells in multicellular organisms form communication networks in order to maintain tissue integrity and stability. One key question is how individual cells present compatible surface protein codes to help coordinate correctly differentiated states. We design and construct novel chemical tools to capture surface proteins for proteomics analysis, followed by validation in human cell models. Understanding cell identity control by characterising signalling networks will enable the identification of new bioactive combinations capable of delivering the desired biological effects without the resistance issue that has become a persistent problem in drug discovery and development. This approach based on cell reprogramming, rather than just cell destruction, could open new windows of opportunity for finding new therapeutic paradigms as well as tools for tissue regeneration or repair.