Sneaky synthetic molecules pave the way for new types of drugs and a new startup

An illustration shows how custom-made peptide molecules (shown in pink and purple) can slide through a cell membrane. (Image by Ian C. Haydon / UW Institute for Protein Design)

Researchers at the University of Washington have discovered how to create peptide molecules that can slip through membranes to enter cells — and they’ve also launched a company with $50 million in funding to capitalize on the discovery for drug development.

The findings, published today in the journal Cell, could eventually lead to new types of oral drugs for health disorders ranging from COVID-19 to cancer.

“This new ability to design membrane-permeable peptides with high structural precision opens the door to a new class of drugs that combine the advantages of traditional small molecule drugs and larger protein therapeutics,” said senior study author David Baker, a biochemist at University. of the Washington School of Medicine, said in a news release.

The company, called Vilya, was created by Baker and his researchers in partnership with Arch Venture Partners. Vilya says it will license the platform and molecules described in Cell’s research paper and has raised $50 million in Series A funding from a group of investors led by Arch Venture Partners.

“Arch is excited to join forces with David to create an entirely new class of drugs that have never been found in nature,” said Robert Nelsen, co-founder of Vilya and CEO of Arch, in a press release. “It’s incredibly exciting to see real potential for this platform.”

Small molecule drugs—for example, aspirin—are small enough to pass through cell membranes to do their job. Protein therapeutics—for example, monoclonal antibodies—can target more complex diseases, but protein molecules are usually too large to pass through lipid-based cell walls.

Peptide drugs are made from the same building blocks as protein and offer many of the advantages of protein-based drugs. They can bind to protein targets in the body more precisely than small-molecule drugs, promising fewer side effects.

“We know that peptides can be great drugs, but a big problem is that they don’t get into cells,” said study lead author Gaurav Bhardwaj, assistant professor of medicinal chemistry at the UW School of Pharmacy. “There are a lot of great drug targets inside our cells, and if we can get in there, that space opens up.”

The recently reported experiments used some molecular design techniques to create types of peptide molecules that can enter cells more easily.

Most peptides have chemical characteristics that cause them to attach to water molecules rather than slip through a cell’s lipid membrane. First, the researchers made synthetic peptides that were less likely to interact with water. They also designed peptides that could change shapes as they moved through membranes.

More than 180 custom-made peptide molecules were tested on artificial membranes in the laboratory. The researchers found that most of their peptides could pass through lipids. Further laboratory tests, using intestinal epithelial cells, convinced the UW scientists that some of the molecules could make the jump from the stomach directly into the bloodstream.

Even more studies, conducted in mice and rats, showed that some of the peptides could effectively move out of the gut, cross multiple membranes, and enter living cells. Such peptides could theoretically be turned into oral drugs. “These molecules are promising starting points for future drugs. My lab is now working to convert them into antibiotics, antivirals and cancer treatments,” Bhardwaj said.

Bhardwaj said peptide-based drugs could address the challenges posed by antibiotic resistance — and also offer a new strategy to fight COVID-19.

“One of the most obvious drug targets is inside infected cells,” he said. “If we could shut down this enzyme, it would stop the virus from making more copies of itself.”

Bhardwaj and Baker are among several researchers at UW Medicine’s Institute for Protein Design who are part of Vilya’s founding team, along with several representatives from Arch Venture Partners. Steven Gillis, CEO at Arch, is Vilya’s executive chairman. (For what it’s worth, Vilya was the elven ring of power worn by Elrond in JRR Tolkien’s Lord of the Rings saga.)

Vilya takes its place among a series of companies created by researchers at the Institute for Protein Design — a series that also includes A-Alpha Bio, Arzeda, Cyrus Biotechnology, Icosavax, Lyell Immunopharma, Monod Bio, Mopad Biologics, Neoleukin Therapeutics , Outpace Bio (from Lyell), PvP Biologics (acquired from Takeda Pharmaceuticals), and Sana Biotechnology.

Bhardwaj and Baker are among 26 authors of the paper published by Cell, titled “Accurate De Novo Design of Membrane-Traversing Macrocycles.”

The research was supported by The Audacious Project. Gates Ventures? Eric and Wendy Schmidt on recommendation of Schmidt Futures. the Nordstrom Barrier Institute for Protein Design Directors Fund; Wu Tsai Translational Fund; Bill and Melinda Gates Foundation. Takeda Pharmaceuticals; Howard Hughes Medical Institute; Washington State Supplemental Funding. Ministry of Defense; Simons Foundation; Defense Threat Reduction Agency? National Institutes of Health? and the Washington Research Foundation.

This report has been updated with a statement from Vilya.

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