The compounds prevent the abnormal aggregation of the transthyretin protein by holding it together in its functional form.

Researchers at Stanford University and The Scripps Research Institute identified chemical compounds that show promise as potential therapeutics for a set of medical conditions caused by the abnormal clumping together of a protein known as transthyretin (TTR). The compounds, which prevent the abnormal aggregation of the TTR protein, work by holding the protein together in its functional form. The scientists suggest that these compounds may have the potential to help people who have TTR-related amyloid diseases or are at risk for them, and may have advantages over other TTR-stabilizing drugs that are currently in clinical trials.

“These new compounds have structures that make them very effective at stabilizing TTR in its stable native tetrameric form in laboratory tests, and they also seem nontoxic in cell culture,” said Stephen Connelly, a senior research associate in the Scripps Research laboratory of Professor Ian Wilson. The report appears in the current issue of Science Translational Medicine.

Secreted by the liver into the bloodstream, TTR tetramers work as transporters of the hormone thyroxine and also bind the holo retinal binding protein. In the bloodstream, however, TTR tetramers often come apart, and when that happens, the naturally sticky individual TTR proteins may start to re-form abnormally into toxic fibril-shaped aggregates known as amyloids. The scientists note that it is well known that the body’s normal defenses against amyloids decline with aging.

TTR amyloids can impair functions or hasten age-related degeneration. Inherited mutations of the TTR gene can cause earlier-onset TTR amyloid conditions, including familial amyloid cardiomyopathy, which can lead to heart failure.

First-generation drug candidates for preventing TTR amyloid formation have been developed, and two are already in clinical trials, the investigators report. Most of these have chemical similarities to nonsteroidal anti-inflammatory drugs (NSAIDs). As such, the researchers say that they have potentially harmful side effects—including to the heart and kidney—that would make them less than ideal for long-term use, especially in patients with compromised heart function. For this reason, the team developed a test to screen a library of compounds for those that would bind and stabilize TTR bu,t otherwise, would not have NSAID-like effects.

They found 33 TTR stabilizers with their screening system. “Many of these were novel chemical entities with no previously known biological targets,” says Isabella Graef, assistant professor of pathology at Stanford University. After selecting the most potent of the compounds, she and her team used further lab tests to confirm the compounds’ effectiveness at preventing amyloid formation by normal and mutant forms of TTR. Preliminary tests of the compounds’ toxicity also showed that they did not appear to harm normal cells.

Graef brought four of her best TTR-stabilizing compounds to Scripps Research for structural analysis. Using x-ray crystallography techniques, Connelly determined the structures of the four compounds as they bound to TTR. “Despite their diverse chemical differences, all four turned out to bind to the TTR tetramer in ways that span, and thereby, strengthen its weaker joints, stabilizing the healthy tetrameric form,” said Connelly.

Graef and her colleagues at Stanford now are trying to gather more data on the effectiveness and safety of the more promising compounds. “Together with physicians from a cardiovascular clinic here at Stanford, we’re investigating whether these compounds can stabilize, in a solution of blood serum, the TTR proteins of patients with a common familial amyloid cardiomyopathy mutation,” she said. “If it can, then hopefully the pharmaceutical industry will want to develop it from there.”

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