Combating Heart Disease Through Chemistry
Four Hamilton students and Associate Professor of Chemistry Max Majireck recently partnered with a Utica-based biomedical research institute to pioneer safer and more sustainable methods for creating therapeutic proteins which, when used as imaging tools, could revolutionize the way life-threatening diseases are detected.
Hamilton teams with MMRI on research
The Hamilton team — Kimberly Chase ’24, Josef Kubofcik ’24, Ryan Rahman ’24, and Luke Cohen-Abeles ’23 — collaborated with Utica’s Masonic Medical Research Institute (MMRI), a prolific hub for biomedical research located only a few minutes from campus. Conceived to diagnose a cardiovascular disease called atherosclerosis, the new process produces useful peptide molecules without the detrimental byproducts of other synthesis methods.
The Hamilton-MMRI research team discovered a method for creating therapeutic proteins (FTP11 molecules) that “avoids the use of toxic compounds, called oxidants, that are generally required to accomplish this reaction,” Max Majireck said. Instead, the new method employs a sonicator, a machine that agitates particles through sound waves.
Atherosclerosis is among the most common causes of death in the world and is the leading cause of death in the U.S. It is caused by the accumulation of plaque on the walls of arteries. This buildup restricts blood flow, causing arteries to narrow and harden, in some cases leading to blood clots, heart attacks, or strokes. While this often occurs in the heart, atherosclerosis can affect any arteries in the body.
“We dissolve our compound in a relatively small amount of solvent and hit it with some sound energy, which we think helps mix in oxygen important for the chemical reaction,” Majireck explained.
How peptides become an “imaging tool”
The oxygen is necessary to create a disulfide bridge, a crucial stage of peptide synthesis. While they do not treat atherosclerosis, FTP11 peptides can be attached to dye and used to image fibrin and platelet deposition in arteries. Fibrin proteins and platelet cells are two of the main components of blood clots. Thus, FTP11 is an “imaging tool,” used for diagnosing at-risk patients, Rahman said.
One key step in the reaction is cyclization. According to Majireck, this occurs at the very end of synthesis when the peptides form a ring with one end of the molecule binding to the other. “It’s a lot more complicated than this,” he noted, “but it’s almost like a string becoming a circle.”
Using high-tech equipment
To know when cyclization is complete, the team used a High-Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS) machine to measure the composition of chemicals. They took aliquots, or representative samples, from their reaction mixture and placed them into the HPLC-MS, which then indicated what percent of the peptide had been cyclized.
Fat, cholesterol, and other substances compose the plaque responsible for atherosclerosis. Because no symptoms present themselves until the condition is quite severe, it is best to be proactive: while atherosclerosis is treatable by medication, maintaining a healthy lifestyle helps reduce the risk of dangerous plaque buildup.
The initial observation that this method was possible occurred at MMRI. From there, the Hamilton team focused on developing the FTP11 peptides that could later be adapted for medical purposes. “My lab develops new chemical reactions,” Majireck said. To facilitate these reactions — in this case, the formation of disulfide bridges — the students were mainly responsible for preparing the peptide samples, setting up the HPLC-MS, and monitoring the cyclization status.
“[The students have] become experts on using some of the necessary instrumentation and some of the experimental methods that we used.”
Thanks to their involvement in every step of the research process, the students became competent users of machines like the HPLC-MS, which would not typically be used for regular coursework. “They’ve become experts on using some of the necessary instrumentation and some of the experimental methods that we used,” Majireck said. “They did a lot of this on their own.”
Chase stressed the value of this experience. “We learned a lot of new techniques and worked with equipment different from anything I’d used before … I’m really thankful I was able to get this opportunity,” she said.
Existing atherosclerosis treatments that use FTP11 peptides may rely on production methods involving toxic compounds. The new process synthesizes these molecules in a more efficient and eco-friendly way. Once developed, FTP11 proteins can be used to identify dangerous plaque buildup.
Long-term collaboration for Hamilton and MMRI
Reflecting on the relationship between MMRI and Hamilton, Majireck described how the project has “fostered a collaboration that we hope is going to be longer term.” While developed this summer in relation to atherosclerosis, this improved synthesis method has shown to be effective for other applications as well, Cohen-Abeles noted.
MMRI has already begun working on these other applications — with Hamilton not far behind. “The best research begets more research,” Majireck said. “When we figure out how to optimize this reaction for the peptides we’re working on now, we’ll likely work on expanding into different peptides.”