The research work in the Loh research group draws upon nature inspired non-covalent catalysis and emerging catalytic concepts to advance carbohydrate chemistry. Of particular focus is our fundamental interest in mechanistic elucidation to understand intricacies of glycosylation pathways. Our multidisciplinary approach in combining synthesis and cell-based phenotypic assays opens up a plethora of opportunities to answer fundamental questions at the interface of carbohydrate chemistry and chemical biology.
Our research direction is currently divided into the following 3 strategic lines:
a) Development of Biomimetic Concepts in Glycosylations
Inspired by how enzymes such as glycosyl-transferases perform precision stereocontrolled chemistry simply by the use of hydrogen bonds, we are particularly interested in investigating how noncovalent concepts such as hydrogen bonding (HB) and halogen bonding (XB) modulate glycosylations. Currently, our young research group has successfully published our seminal reports demonstrating the power of HB and the XB catalysis to construct glycosidic bonds via versatile strain-release glycosylations.
Particularly, we have also developed a generally applicable multicatalysis diversification concept termed SLICK (Sugar-Linker-CLICK), where a one-pot sequential catalytic operation provides rapid diversification into structurally diverse glycosides.
b) Mechanistic Investigations via Kinetics Studies
We are interested to advance carbohydrate chemistry by unraveling the mechanistic intricacies via rigorous in-situ monitoring and kinetics analysis. Our mechanistic driven approach is a powerful tool that enables us to dissect the mechanistic underpinnings of strain-release glycosylations, and critical in opening up new frontiers like our published multi-staged operations of XB catalysts.
c) Accessing Novel sp3 rich Glycosidic Chemotypes and Deconvoluting Novel Biological Activity
As new generational organic chemists, we are enthusiastic in applying our expertise in synthesizing unnatural glycosides and bridge it to real life biological applications. We are currently pursuing a strong interfacial programme, combining our synthesis and chemical biology knowledge, via a forward chemical genetics approach , to exploit phenotypic screens as a powerful tool to discover new glycosidic analogues that have potential applications in oncology (cancer).
Currently our analogues derived from XB catalyzed strain release glycosylation, and our SLICK methodology has proven effective in inhibiting the Hedgehog (Hh) Signaling Pathway. More significantly, using chemical biological techniques such as cell based assays, fluorescence activated cell sorting (FACS), fluorescence and confocal microscopy, we established that our strain-release glycosides define a new class of non-Smoothened Hh inhibitors.