Biomedical engineers at Duke University have shown that the effectiveness of a two-pronged type 2 diabetes procedure improves when the medications are attached to each other by a heat-sensitive tether rather than simply administered at the same time. The combination molecule is formed by an elastin-like polypeptide (ELP) linker which, when injected under the skin, forms a gel-like depot that slowly dissolves and releases the active substance over time.
This innovative approach features the widely prescribed type 2 diabetes medication glucagon-like peptide-1 ( GLP-1) and the convincing drug candidate fibroblast growth factor 21 (FGF21), which together establish tight glycemic regulation and a successful weight reduction in diabetic mice.
Since GLP-1, a short peptide, and FGF21, a large folded protein, are such different compounds, these results indicate that this combination drug design approach may be extended to disease therapies beyond diabetes.
"Researchers mainly unite drugs that are similar in size, structure and function in the emerging field of multi-functional single-molecule diabetes drug design," said Caslin Gilroy, a postdoctoral scholar at the University of California , Berkeley, who led the project while completing her PhD in Biomedical Engineering at Duke. "It is a major technical accomplishment to be able to combine these structurally distinct drugs into a single molecule while preserving the bioactivity and stability of each." Although there are many therapeutic options, a single medication is rarely able to treat an advanced case.
A a class of drugs is based upon GLP-1, a naturally occurring peptide released after a meal from the intestines. Researchers are studying hybrid therapies that strategically combine GLP-1 with additional medicines to improve regulation of glucose, reduce side effects and increase weight loss.
While most drug combinations contain small peptides from the same family as GLP-1, the Alan L combines Gilroy and Ashutosh Chilkoti.
"FGF21 acts through a mechanism different from GLP-1, and we hypothesized the two drugs will complement each other nicely,"Gilroy said. "GLP-1 increases pancreatic insulin secretion while FGF21 enhances insulin response in the body.
But instead of merely injecting diabetic mice with both medications at the same time , the researchers opted to combine GLP-1 and FGF21 into a single molecule. A single drug is also advantageous for the prescribing physician and patient, as it decreases the cost of medication and simplifies the treatment regimen.
However, GLP-1 and FGF21 are both peptide-based drugs, which rely heavily on shape and surface function.
The researchers turned to the ELP — a specialty of the Chilkoti research community to form one drug out of two. This condition offers versatility, allowing drugs fused in the room at either end of the ELP to do their respective jobs.
"Linking the drugs to an ELP enables us to develop a compound that is liquid at room temperature but that forms a gel-like depot upon injection," Gilroy said. "The depot dissolves over a period of at least one week, slowly and periodically releasing the drug into the system over time."
Results show that drug levels in the system remained stable while blood sugar levels were reduced to a safe level and sustained for up to 10 days after a single dose. Mice treated with the GLP-1 / FGF21 combination drug were better able to recover from a glucose challenge compared to either drug alone and were the only control group to lose weight during the control.
The combination of drugs also performed better when GLP-1 and FGF21 were linked together rather than administered as a mixture of individual drugs. Researchers assume that connecting them means that GLP-1 and FGF21 both function together at the same time , allowing their mechanisms of action to synergize and operate together. "It was always just a hope at the beginning of this project.
This article was first posted on https://pratt.duke.edu