An oral prodrug has been developed which uses artificial sweeteners to deliver a protective carbon monoxide dose which protects against acute kidney injury.
Although carbon monoxide (CO) gas is toxic in large doses, with some 50 000 people suffering CO poisoning each year in the US, scientists have discovered it can reduce inflammation and protect cells against injury. The protective effects of CO against injury in the kidneys, lungs, gastrointestinal tract and liver, among other organs has been shown in previous research. For the past five years, Wang and his collaborators have worked to design a safe way to deliver CO to human patients via prodrugs, which are inactive compounds that must undergo a chemical process in the body to release the active pharmacological agent. Their paper was published in Chemical Science.
Using two common artificial sweeteners, saccharine and acesulfame, as ‘carrier’ molecules for a prodrug, Prof Wang’s team were able to create an oral administration route for CO. They designed the molecules to release CO as they decomposed from water exposure. These are the first examples of orally active, organic CO prodrugs using a benign carrier that is approved by the Food & Drug Administration with a demonstrated safety profile.
“It’s difficult to deliver a gas, much less a poisonous gas, as a therapeutic to patients, and this work represents a pivotal step forward in developing alternative delivery forms,” said Prof Wang, a Georgia Research Alliance Eminent Scholar. “We wanted to work with a carrier that has a very well characterized safety profile, which confers a higher degree of certainty that it will be safe to use in a pill for human consumption.”
The scientists tested one of the prodrugs, CO-306, for pharmacological efficacy against acute kidney damage. CO-306, which uses saccharine as a carrier molecule, was administered to mice and it was found that it reduced biomarkers for kidney injury, indicating it could be developed working therapy. The type of kidney injury modelled mimicked those in humans that occur with extensive muscle damage, sickle cell disease, a common type of malaria, cardiopulmonary bypass surgery and severe sepsis.
Further animal model studies and safety assessments on CO-306 are planned by Wang and colleagues before they progress to human clinical studies. They also plan to test CO-306 for efficacy against other types of organ injuries.
Additionally, CO-based therapies hold promise as a method of reducing the likelihood of organ damage during transplantation and improving outcomes for transplant patients, according to Prof Wang.
“Science shows that exposing organs to CO gas can help preserve organs and prevent them from deteriorating during the process of transplantation,” he said. “Now we need to demonstrate that these prodrugs can have a similar effect.”
Source: Georgia State University
Journal information: De La Cruz, L. K., et al. (2021) Adapting decarbonylation chemistry for the development of prodrugs capable of in vivo delivery of carbon monoxide utilizing sweeteners as carrier molecules. Chemical Science. doi.org/10.1039/D1SC02711E.
