Director, Graduate Department of Pharmaceutical Sciences
Director, Pharmaceutical Chemistry Specialist Program
Novel DNA Structures
Protein folding, gene regulation, drug interactions, and membrane formation depend on the ability of structurally correct complexes forming at the right time and place within a cell. The research in my laboratory is directed toward understanding the role of non-covalent interactions in determining the structural stability of macromolecular complexes, especially those involving complexes with DNA.
The results of this research are important to the under-standing of the physical basis for biological regulation, the origin of some diseases, and for the development of new drugs. The research is multi-disciplinary, involving techniques and principles of biochemistry, kinetics, molecular biology, physical chemistry and spectroscopy.
There are three lines of research in the laboratory:
- The physical chemistry of complexes formed with DNA. The formation of a DNA-protein complex is the result of many non-covalent contacts; these may involve electrostatic, hydrogen bonding, or hydrophobic interactions. An individual contact may enhance or diminish the overall stability of the complex. Under-standing the relative importance of the contacts to the formation of the DNA-protein complex is of fundamental importance to elucidating the molecular mechanisms of genetic regulation. This knowledge would also be useful in designing new drugs that can interact with DNA in a desired manner. We are investigating the complex DNA forms with proteins, peptides and small drugs using several experimental approaches.
- Formation and Structural Determinants of Non-canonical DNA Structures. The ability to therapeutically control genetic expression by introducing synthetic oligonucleotides into cells is called antisense or antigene therapy. The fundamental interactions in these novel therapies involve unusual DNA structures such as three- and four-stranded DNA structures. An example of an unusual DNA assembly is our recent discovery of multi stranded DNA species that we have called frayed wires. To fully realize the potential of the new methods, we are studying the chemical, physical and biological characteristics of a variety of non-standard DNA structures.
- Novel Sterilization Technologies. Sterilization is an important step in the manufacture of dosage forms and medical devices. However, the extreme requirements needed to assure elimination of all micro-organisms is often incompatible with the sensitivity of pharmaceuticals and medical devices to the sterilization conditions. We are developing new methods of sterilization based upon the use of elevated hydrostatic pressure.
Leslie Dan Faculty of Pharmacy
University of Toronto
144 College Street
Toronto, Ontario, M5S 3M2