Wagner Research Group

The goal of our laboratory is to apply the principles of chemical biology and medicinal chemistry to the design of new chemical and cell based therapies by:

• Applying chemical induced dimerization to guide the self-assembly of protein nanorings that can be used for drug delivery, tumor imaging and the targeting of immune and stem cells for tumor targeting or tissue regeneration.

•  Designing therapeutic nucleotide prodrugs that can be targeted too and activated by diseased tissues.

•  Uncovering the natural function of Hint proteins and applying our knowledge to the design of anticancer, antiviral drugs and new pain medications.


Research

Chemically Self-Assembled Nanostructures

Our laboratory has developed a method for the engineering and preparation of chemically self-assembling nanorings  (CSANs) that can display targeting peptides and proteins, such as single chain antibodies (scFvs) that can be used for drug delivery, imaging and cell surface engineering.  



Design of Therapeutic Nucleotide Pronucleotides

Nucleosides and nucleotide analogs have shown great therapeutic potential and utility for the treatment of cancer, comprising 20% of FDA approved anti-cancer drugs and 50% of the FDA approved anti-viral drugs, Currently, fourteen nucleosides are clinically used for the treatment of cancer, with several others under clinical development. 

Histidine Triad Binding Proteins (HINTs) are conserved from bacteria to human and are considered to be the ancestor of the histidine triad protein (HIT) superfamily. Humans express three HINTs: hHINT1, hHINT2 and hHINT3. Our laboratory has shown that hHINTs act as nucleoside phosphoramidate monoester and acyl-adenylate hydrolases and are therefore the likely intracellular enzymatic activators of nucleoside phosphoramidates.


Design of Nucleotidomimetic Translational Control Tools

Translation initiation can occur by internal ribosomal entry or by cap-dependent means. The first steps in this process depends on the assembly of a trimolecular cap-binding complex designated eIF4F, which consists of eIF4E, eIF4G, and eIF4A. Translational control is usually exerted by regulation of the abundance and activity of eIF4E, which binds the 5' methylguanosine cap of mRNA (7-methyl-G(5')ppp(5')N where N is any nucleotide). Since the abnormal over-expression of eIF4E has been associated with tumor tissues, the down regulation of cap-dependent translation should revert the transformed phenotype.