Research Synopsis

 

The goals of our bioorganic chemistry program are to design and synthesize small molecules and small molecule probes with desired biological activities and understand their structure activity relationships and target interactions.


We currently have three NIH funded programs. The first program includes the synthesis and study of enzyme inhibitors in the trehalose utilization pathways of Mycobacterium tuberculosis (Mtb). Mtb is the infectious etiological agent of tuberculosis (TB). Mtb is estimated to infect up to one third of the world’s population, of those people about eight million develop an active infection. About 1.4 million people die of TB every year. Further, extensively drug resistant strains of Mtb have emerged making many cases of TB difficult, if not impossible, to treat. Thus, there is an urgent need to discover small molecule probes that can be used to study or identify essential enzymes in Mtb. Our studies may lead to therapies to treat TB. Specifically we are discovering and evaluating new covalent and non-covalent glycoside hydrolase and esterase inhibitors.  


A second exploratory program is related to the synthesis of Mtb-active marine natural products which show improved selective activity against non-replicating Mtb. The new derivatives can also be used to generate chemical probes which will be used in combination with chemical biology methods for the identification of new biological targets. These studies are anticipated to be useful for identifying next generation anti-tubercular agents.


The third program involves the use of antibody recruiting molecules (ARMs) to generate improved immunotherapeutics. Vaccines can be improved by directing antigens via the use of ARMs and natural antibodies to antigen presenting cells (APCs).  We have used this approach to improve antibody and T-cell responses against tumor associated-antigens (TAA) in mice. We are currently working to demonstrate this effect for other antigens such as bacterial antigen. A second aspect of this program is the development of methods for vaccine and antigen synthesis.


These programs are highly collaborative and allow students interactions with structural biologists, microbiologists, immunologists, and natural product experts

 
 
 New pyrrolidines designed to interact with a glycoside hydrolase-like enzyme.

New pyrrolidines designed to interact with a glycoside hydrolase-like enzyme.

 Aminothiophenes with potent anti- Mtb  Activity

Aminothiophenes with potent anti-Mtb Activity

 The use of L-Rhamnose as an antibody recruiting molecule (ARM) to enhance antibody and T-cell responses to antigens. 

The use of L-Rhamnose as an antibody recruiting molecule (ARM) to enhance antibody and T-cell responses to antigens. 

 Methods to prepare antigens from within the lipopolysaccharide of   P. aeruginosa.    

Methods to prepare antigens from within the lipopolysaccharide of  P. aeruginosa.

 

 

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