Research

Research in the Harki laboratory focuses on the design, synthesis and biophysical characterization of novel small molecules that influence cellular function.  Applications for these molecules range from anticancer drug discovery to new tools for modern biotechnology research.  Our core science is organic chemistry. However, we use techniques of modern molecular biology, genetics, and genomics to probe the biological activities of the compounds we synthesize. Two ongoing projects in the laboratory are described below.

Development of Chemical Probes of Enzyme Enantioselectivity:
Applications in Cancer Drug Discovery

We are investigating the molecular interactions between cellular enzymes and nucleotide substrates that define enzyme enantioselectivity.  This work is inspired by the therapeutic utilities of L-nucleoside antiviral agents and the lack of analogous anticancer L-nucleosides.   We are utilizing a series of D- and L-enantiomer nucleosides and nucleotides to probe the enantioselectivity of guanosine monophosphate synthetase (GMPS), a key enzyme in de novo guanosine monophosphate biosynthesis.  We aspire to transition the knowledge learned from this study towards the design of candidate L-nucleoside GMPS inhibitors for applications in cancer chemotherapy.  

 Regulating NF-κB-Activated Gene Expression with Natural Product Analogues

A second project in the laboratory is evaluating structure-function relationships of two sesquiterpene lactone (SL) natural products, helenalin and parthenolide.  These compounds are micromolar inhibitors of the pro-inflammatory transcription factor NF-κB and possess unique biological functions: helenalin is selective for p65 protein, which is uncommon for SL NF-κB inhibitors, and parthenolide was recently shown to exhibit selective toxicity towards cancer stem cells.  In addition to optimizing their biological activity and probing their cellular targets, we aspire to optimize their NF-κB inhibitory activity for future development as anticancer agents.