Heart repair factor boosted by RNA-targeting compound

Heart repair factor boosted by RNA-targeting compound


A heart attack can leave parts of the heart permanently scarred and stiff, resulting in prolonged disability and potential progression toward heart failure. Scientists have studied various ways to repair or regenerate such damaged heart tissue, with limited success.

A new study shows that by targeting an essential biomolecule that surges in failing heart muscle, it may be possible to one day heal damaged heart tissue with medication.

In a study published in the journal Nature Chemistry, the authors describe the discovery of the first compounds able to restart cellular production of a factor called VEGF-A, short for vascular endothelial growth factor A, in cellular models. Research over many years has shown VEGF-A acts as a signal to stem cells, causing them to rebuild blood vessels and muscle in damaged heart tissue, and improve blood flow.

Targeting RNAs, the "middleman" between genes and protein production, makes logical sense, but doing so with medicines was once deemed unfeasible. RNAs were long thought to be poor small-molecule drug targets due to their simple four-base makeup and dynamic shape. Through the years, the authors have developed an array of computational and chemical tools designed to overcome those barriers.

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

Lead author analyzed the genomics underlying VEGF-A production to assess optimal RNA drug targets. The team selected a microRNA precursor called pre-miR-377, finding it acts like a dimmer switch for VEGF-A production in failing heart muscle.

They then used computational and chemical tools, in conjunction with a diverse set of compounds from AstraZeneca's collection, in search of chemical partners able to selectively bind to the key conserved structural features of pre-miR-377.

"A remarkable on-target specificity is achieved by combining the active compound with other helper molecules," the lead explains.

Other strategies that have been attempted to boost VEGF-A production include administration of VEGF-A itself, or delivery of messenger RNA that encodes for the protein.

"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," the senior author says.The compound has, so far, been tested in cells, not whole-animal models of heart failure, the author notes.

"We delivered a lead small molecule compound to reprogram the cell's software to force it to re-express VEGF-A," the senior author says. "Transforming TGP-377 into a potential medicine that reaches patients will take considerably more time and research."

Because of the large scale screening done to identify TGP-377, the author says the group expanded by 20-fold the data set of known RNA-binding small molecules generally, with implications for multiple incurable diseases.

"There are potential RNA drug targets for nearly every disease." The author says. "We now have a much greater toolbox to search for lead molecules with medicinal potential."

https://www.nature.com/articles/s41557-020-0514-4

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