Study reveals key biomolecule that can heal damaged heart tissues

When a person suffers a heart attack, parts of the heart can become irreversibly stiff and scarred, leading to persistent disability and possible progression toward heart failure.

Study reveals key biomolecule that can heal damaged heart tissues
Chemistry professor Matthew Disney, PhD, in his lab at Scripps Research in Jupiter, Florida. Disney and his graduate student, Hafeez Haniff, developed a compound that acts on non-coding RNA to restart a healing factor silenced by heart attack. Image Credit: Scripps Research Institute.

Researchers have explored numerous ways to regenerate or rectify such damaged heart tissues, but had only limited success.

Matthew Disney, PhD, a Chemist from Scripps Research Institute, performed a new study that demonstrated that damaged heart tissues could be healed by drugs by targeting a crucial biomolecule that surges in failing heart muscles.

In a study published recently in the Nature Chemistry journal, the Disney collaboration explained the finding of the first compounds that are capable of restarting cellular production of a factor known as vascular endothelial growth factor A, or VEGF-A for short, in cellular models.

Studies performed over several years have demonstrated that VEGF-A serves as a signal to stem cells, allowing them to reconstruct muscles and blood vessels in impaired heart tissues, and also enhance blood flow.

While it sounds plausible to target RNAs—the “middleman” between genes and protein synthesis—doing so with drugs was once believed to be unfeasible. For a long time, RNAs were thought to be poor, small-molecule drug targets because of their dynamic shape and simple four-base makeup.

Disney and collaborators have now created a range of chemical and computational tools developed to overcome those obstacles.

During a heart attack, the injury causes proteins that could promote new, healthy blood vessel growth to go silent. We analyzed the entire pathway for how the protein is silenced, and then we used that information to identify how to reinvigorate its expression.”

Matthew Disney, PhD, Chemist, Scripps Research Institute

In association with scientists at AstraZeneca, Hafeez Haniff, the study’s lead author and a graduate student from Scripps Research Institute in Florida, examined the genomics underlying the production of VEGF-A to evaluate optimal RNA drug targets.

The researchers chose a microRNA precursor, known as pre-miR-377, after discovering that it serves similar to a dimmer switch for the production of VEGF-A in failing heart muscles.

They subsequently employed Disney’s chemical and computational tools, in combination with a varied set of compounds from the collection of AstraZeneca, to look for chemical partners that can selectively attach to the crucial conserved structural traits of the pre-miR-377 microRNA precursor.

Haniff stated, “A remarkable on-target specificity is achieved by combining the active compound with other helper molecules.”

Scientists have attempted other strategies to increase the production of VEGF-A; these include delivery of messenger RNA that encodes for the protein, or administering the VEGF-A itself.

Each of these approaches uses large compounds that can have limited distribution to diseased tissues, compared to potential specific, RNA-binding small-molecule lead medicines.”

Matthew Disney, PhD, Chemist, Scripps Research Institute

To date, the compound has been verified in cells, but not whole-animal models of heart failure, noted Disney.

Disney further added, “We delivered a lead small molecule compound to reprogram the cell’s software to force it to re-express VEGF-A. Transforming TGP-377 into a potential medicine that reaches patients will take considerably more time and research.”

Disney named their success a “test case” that demonstrates that medicinal compounds could be predictably and reliably developed for pre-defined RNA targets and could induce the production of proteins in cellular models.

According to Malin Lemurell from AstraZeneca, this is a potentially significant first step.

The ability to design small molecules capable of interacting with and modulating RNA could open new avenues to target challenging disease pathways that have previously been considered undruggable. This research has enabled the generation of quality tool compounds that will be useful to probe this mode of action further.”

Malin Lemurell, Head of Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca

Due to the large-scale screening performed to detect TGP-377, the team expanded the data set of familiar RNA-binding small molecules by 20 times, with implications for various incurable diseases, Disney added.

There are potential RNA drug targets for nearly every disease. We now have a much greater toolbox to search for lead molecules with medicinal potential,” concluded Disney.

Source:
Journal reference:

Haniff, H. S., et al. (2020) Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold–small molecule interactions. Nature Chemistry. doi.org/10.1038/s41557-020-0514-4.

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