A $700,000 grant from the National Science Foundation has enabled UNCW’s Department of Chemistry and Biochemistry to acquire a 600 MHz nuclear magnetic resonance (NMR) spectrometer. It permits researchers to investigate the nature and effects of chemical interactions more accurately and with greater sensitivity.
The new NMR was required to fulfill current and future research and teaching needs. It will augment the department’s aging 400 MHz NMR and will be used not only by chemistry and biochemistry faculty but also by biology faculty and researchers at the Center for Marine Science.
Now, UNCW researchers and their students have access to the new NMR and to new differential scanning and isothermal calorimeters that augment more than $2 million of sophisticated experimental and computational chemistry department resources, including electrochemical analyzers, a gas chromatograph-mass spectrometer (GC-MS), ultra-violet-visible (UV-VIS) spectrophotometers, Fourier Transform infrared (FTIR), fluorescence, optical emission and atomic absorption spectrometers, gas and liquid chromatographs, and soon, two Liquid Chromatography Mass Spectrometry (LC-MS) systems.
These three projects seek answers to questions such as, “How can anti-cancer drugs be delivered to specific sites?” “What peptide-based drug delivery design will best carry antibiotics and toxic molecules to targeted cells?” and “What rains back on us?”
The Ties that Bind: Ligands*
*a molecule or group which binds to another (usually macromolecule) with a high degree of specificity.
Ligands could be called the middle linebackersof therapeutic drug delivery — opposing advancing cancers and other seemingly intractable diseases. Using NMR technology to read the molecular structure of DNA, associate professor of chemistry Sridhar Varadarajan designs ligands to deliver knock-out drugs to rapidly growing cancers. His research is also applicable to the treatment of autoimmune diseases such as juvenile diabetes.
Cancer: A Moving Target
“Cancer is really a number of diseases — multiple things have to go wrong in a cell for it to become cancerous,” Varadarajan says. “Each cancer has to be addressed differently.Good cell-targeting ligands must bear enough complementarity to their targets to be accepted by cancer cells. Good DNA-binding ligands must bind to specific sites on the DNA within these cancer cells to deliver the lethal blow.”
The diversity of types of cancer as well as the variety of possible targets and outcomes makes ligand design for drug delivery a very sophisticated task.
“We are testing compounds that can target cancer cells with pure DNA,” Varadarajan says, “and if these compounds bind to DNA and cause damage where we need it, we can destroy the cancer cell without harming healthy cells.”
Current DNA-damaging drugs used for cancer chemotherapy do damage to both normal and cancerous cells. While this damage kills the cancer cell, damage done to normal cells can sometimes lead to mutations, which can cause secondary cancers. Also, the damage experienced by rapid-growing normal cells leads to chemotherapy side effects such as hair-loss and gastric irritation.
Varadarajan has identified an agent Me-lex (1) that efficiently kills cells. He is attaching cell-targeting ligands to this agent so it can be delivered selectively and efficiently to only cancer cells. Most importantly, even if Me-lex should enter normal cells, it will not cause mutations.
These drugs, currently being developed in the Varadarajan lab, have the potential to minimize side effects of cancer chemotherapy while effectively eliminating the occurrence of secondary cancers.
“Me-lex achieves its remarkable selectivity due to its design, the product of years of collaborative work, and places the damage within a particular groove of DNA at specific sequences,” Varadarajan says.
However, Me-lex lacks “tissue specificity” and needs assistance in recognizing cancer cells. Varadarajan, his colleagues and students are attempting to design a ligand able to recognize, in this case, breast cancer cells, and deliver the drug to destroy only the tumor.
“We are attempting to confer tissue-specificity to Me-lex by tethering it to cell-targeting ligands that can bind to a unique receptor or protein on the target cell,” he says.
What NMR Technology Can Do
The 600 MHz NMR, with its larger magnet, offers better resolution and more detailed spectra — graphic read-outs of peaks and ridges — that signify distinguishing chemical shifts and other properties. These spectra reveal the structure of proteins and nucleic acids key to successful ligand design. The technology also gives researchers information on the binding strength of a potential ligand-DNA interaction.
“The sensitivity and dispersion afforded by the 600 MHz NMR, which provides enhanced carbon (13C) sensitivity, is critical for this work,” Varadarajan says.