New Compound Targets Beta Amyloid and Tau Peptides

TRV 101, from Treventis Corp., may prevent the formation of beta amyloid.
TRV 101, from Treventis Corp., may prevent the formation of beta amyloid.

WASHINGTON — Data presented at the Alzheimer's Association International Conference 2015 suggest that a new compound TRV 101 may inhibit protein misfolding of beta amyloid and tau peptides, which contribute to the pathology of Alzheimer's disease.

“Because both beta amyloid and tau contribute to the pathology of Alzheimer's disease, having compounds which can inhibit the formation of oligomers of both proteins would be transformative for treatment,” study investigator Marcia Taylor, PhD, of Treventis Corporation, Toronto, said in a statement. “We have created compounds, such as TRV 101, that are capable of preventing beta-amyloid, tau, or both from forming oligomers in a test tube.”

For the study, Taylor and colleagues aimed to design and develop a small brain-penetrable molecule that targets protein misfolding in general and in both beta amyloid and tau. After screening more than 11 million compounds in a computer model and creating a library of compounds that may prevent toxic protein-protein interactions, they identified a family of novel compounds, of which TRV 101 was a representative compound.

Researchers used biotin-beta-amyloid and biotin-tau assays to measure the efficacy of TRV 101 in preventing oligomerization in vitro, and surface plasmon resonance to determine binding of TRV 101 to beta amyloid and tau 4NR2[KT3] . Researchers also collected in vitro ADMET data and mouse pharmacokinetics/bioavailability.

Results suggested that TRV 101 prevents oligomerization activity against both beta amyloid and tau, and selectively binds to the target protein. Researchers also concluded that TRV 101 has optimum drug-like properties — exhibiting favorable in vitro ADMET, high-brain penetrance, and oral bioavailability — and is benign, according to a 44-receptor panel test.

Taylor said that having a compound that is capable of preventing; peptides from forming oligomers could allow natural clearing mechanisms to remove existing protein aggregates and improve cognitive function.

“We are currently testing our compounds in animal models to verify if we can reduce the levels of oligomers in the brain,” she said.

Reference

Taylor M, et al. Abstract #5230. Inhibition of protein misfolding by optimization of small molecules targeted to both beta-amyloid and tau peptides. Presented at: Alzheimer's Association International Conference 2015; July 18-23, 2015; Washington, D.C.

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