Researchers at Duke University have found that the efficacy of a 2-pronged type 2 diabetes (T2D) treatment increases when the drugs are linked by a heat-sensitive tether rather than simply being concurrently administered, according to a press release.

The combination molecule is formed by an elastin-like polypeptide (ELP) linker that forms a gel-like depot when injected under the skin, which slowly dissolves and releases the active drug over time, according to the study. This approach included the commonly prescribed T2D drug glucagon-like peptide-1 (GLP-1) and the compelling drug candidate fibroblast growth factor 21 (FGF21), which together create tight glycemic control and potent weight-reduction in diabetic mice, according to the study.

The findings suggest that this approach to combination drug design could be applied to disease therapies beyond diabetes, since GLP-1 is a short peptide and FGF21 is a large folded protein, according to the study authors.

"In the burgeoning field of multi-functioning single-molecule diabetes drug design, researchers primarily unite drugs that are similar in size, structure and function," said study lead Caslin Gilroy, a postdoctoral scholar at the University of California, Berkeley, in a press release. "Being able to combine such structurally distinct drugs into a single molecule while maintaining the bioactivity and stability of each is a big technological achievement."

The researchers linked GLP-1 and FGF21 together into a single molecule, since a single molecule is more predictable in how it will disperse through the body, acting on its target tissues before eventually being cleared, according to the study authors. In addition, a single drug is also beneficial for the prescribing physician and patient, as it reduces the medication burden and simplifies the treatment regimen, according to the study authors.

Using an ELP, the researchers were able to form 1 drug out of 2 due to its highly disordered chains of repetitive peptide sequences. Further, the modularity of ELPs also make them highly tunable, allowing for the design of the best delivery system possible. An ELP-based delivery also helps to address the short half-life and needle administration of peptide-based drugs.

The study tested a multi-functioning, slow-release molecule after verifying that GLP-1 and FGF21 retain their respective functions and potencies when linked together by an ELP, according to the study authors.

The results showed that levels of the drug circulating the system remained steady while blood sugar levels were brought down to a healthy level and maintained for up to 10 days following a single dosing. The mice who were treated with the GLP-1/FGF21 combination drug were better able to recover from a glucose challenge compared with either drug alone and were the only test group to lose weight during the trial.


The study authors also noted that the drug combination worked better when GLP-1 and FGF21 were tethered together rather than being delivered as a mixture of individual drugs. Linking these drugs guarantees that GLP-1 and FGF21 are always acting in concert at the same point in time, allowing their mechanisms of action to synergize and work together, according to the study authors.

"We had speculated that we may see synergy when we combined GLP-1 and FGF-21 because they have different modes of action," said Ashutosh Chilkoti, PhD, biomedical engineer at Duke University, in a press release. "That was really just a hope at the outset of this project, and we were more than pleasantly surprised when Caslin showed that combining these drugs into a single molecule clearly showed a synergistic therapeutic effect compared to a mixture of the two drugs."

REFERENCE
Tethering together type 2 diabetes drugs increases efficacy of combination therapy. MedicalXpress. https://medicalxpress.com/news/2020-08-tethering-diabetes-drugs-efficacy-combination.html. Published August 26, 2020. Accessed September 23, 2020.