Synthetic peptide molecules open the way for new drugs

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 created a company to take advantage of the discovery for drug development.

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

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

Small-molecule drugs — for example, aspirin — are small enough to slip through cell membranes to do their work. Protein therapeutics — for example, monoclonal antibodies — can target more complex ailments, but the protein molecules are typically too big to wedge their way 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 protein targets in the body more precisely than small-molecule drugs, promising fewer side effects.

“We know that peptides can be excellent medicines, but a big problem is that they don’t get into cells,” said study lead author Gaurav Bhardwaj, an 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 newly reported experiments used a couple of molecular design techniques to create types of peptide molecules that can get into cells more easily.

Cosmic Science

Antibody cocktail just might ward off COVID-19

An international research team led by University of Washington scientists has identified two kinds of “ultrapotent human antibodies” that could go into a drug cocktail for guarding against COVID-19.

  • UW’s David Veesler and Vir Biotechnology’s Katja Fink are the senior authors of the study published online today by the journal Science, which highlights two monoclonal antibodies known as S2E12 and S2M11. The antibodies were found to block SARS-CoV-2, the coronavirus that causes COVID-19, from latching onto molecular receptors on cells in hamsters.
  • An analysis of the antibodies’ molecular structure determined that they block the virus by gumming up its characteristic “spike” protein, which has been a target for many of the vaccines and therapies under development to fight COVID-19. Some of the researchers behind the newly published study, including Veesler, reported a similarly promising antibody called S309 in May.
  • Researchers say such antibodies could be combined in a drug cocktail to guard against the virus evolving to evade any single one of the ingredients. A drug that takes advantage of S309’s effect is already being tested in a phase 2/3 clinical trial launched by GlaxoSmithKline and Vir Biotechnology.

The principal authors of the Science study, “Ultrapotent Human Antibodies Protect Against SARS-CoV-2 Challenge Via Multiple Mechanisms,” are M. Alejandra Tortorici of the University of Washington and Martina Beltramello of France’s Pasteur Institute and CNRS. Other UW researchers among the 47 co-authors of the study include Ha Dang, Matthew McCallum and John Bowen.

This report was first published on GeekWire.


Scientists design proteins that confound coronavirus

Imagine being able to ward off COVID-19 just by spritzing a nasal spray into your nostrils. It may not be just your imagination: Researchers at the University of Washington have designed a batch of synthetic proteins that could conceivably block the coronavirus behind this year’s pandemic from gaining a foothold.

“Although extensive clinical testing is still needed, we believe the best of these computer-generated antivirals are quite promising,” Longxing Cao, a postdoctoral scholar at UW’s Institute for Protein Design, said in a news release.

Cao is the lead author of a study about the protein-building experiment, published today by the journal Science. It’s the latest innovation to come from the emerging field of protein engineering, and the technique could revolutionize how drugs are developed to counter future pandemics.

It may not be too late to counter COVID-19 as well. “We are working to get improved versions … deployed to fight the current pandemic,” senior study author David Baker, the director of the Institute for Protein Design, told GeekWire in an email.

The technique involves creating small-molecule proteins, or mini-binders, that are custom-designed to latch onto the spiky molecular structures that are scattered around the surface of SARS-CoV-2, the virus that causes COVID-19.

The spikes on the virus do their dirty work by fitting into molecular-scale receptors on the surfaces of cells, much like fitting a key into a lock to gain entry to someone’s house. Once the virus “unlocks” a receptor, it gains entry to the cell, hijacks its chemical machinery and churns out more virus particles to spread the infection.

Baker, Cao and their colleagues used high-powered computers to design more than 2 million candidate proteins that could conceivably gum up the works for the virus’ spike protein. More than 118,000 of the most promising candidates were synthesized and tested on lab-grown cells.

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Synthetic proteins use logic to choose which cells to kill

The age of molecular-scale computing is entering a new era, thanks to the development of a system that uses synthetic proteins and Boolean logic to identify cancer cells.

The proteins can lock onto chemical markers on the surface of cells in predetermined combinations, performing the roles of logical AND, OR and NOT gates. It’s similar to the way binary computers do their thing, but with biochemistry rather than electronic bits.

“We were trying to solve a key problem in medicine, which is how to target specific cells in a complex environment,” Marc Lajoie, one of the lead authors of a study published today in the journal Science, explained in a news release.

“Unfortunately, most cells lack a single surface marker that is unique to just them. So, to improve cell targeting, we created a way to direct almost any biological function to any cell by going after combinations of cell surface markers,” Lajoie said.

Lajoie worked on the effort during his stint as a postdoctoral scholar at the University of Washington’s Institute for Protein Design. He’s now co-director for protein and cell engineering at Lyell Immunopharma, a California-based startup aiming to commercialize the technique.

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A-Alpha Bio wins grant to work on molecular glue

Emily Engelhart
Emily Engelhart, a research scientist at A-Alpha Bio, works at the company’s lab in the University of Washington’s Fluke Hall. (A-Alpha Bio Photo)

A-Alpha Bio, a Seattle venture that began at the University of Washington, has won a $620,472 grant from the National Science Foundation to develop a system that identifies molecules capable of taking disease-causing proteins out of circulation.

The Phase II Small Business Innovation Research grant, awarded on April 30, follows up on an earlier Phase I grant focusing on molecular glue. Such molecules are designed to “glue” a target protein onto another type of protein known as an E3 ubiquitin ligase. The ubiquitin molecules serve as chemical tags that basically tell the cell, “Get rid of the protein that I’m connected to.”

“It’s a way to get rid of what would otherwise be more or less ‘undruggable’ protein targets,” A-Alpha Bio CEO David Younger told GeekWire.

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Scientists chart weak spots in coronavirus protein

Coronavirus protein structure
A cryo-EM map of a portion of the novel coronavirus’ protein structure shows several substructures, including a hairpin-shaped protein that hadn’t been identified previously. (Gao et al. / Science / AAAS)

Chinese researchers say they’ve mapped out a key protein structure in the virus that causes COVID-19, including the likeliest target for the antiviral drug remdesivir.

What’s more, they say that same atomic-scale target, known as nsp12, could be attacked by other types of antiviral drugs.

“This target … could support the development of a cocktail of anti-coronavirus treatments that potentially can be used for the discovery of broad-spectrum antivirals,” the researchers write in a paper published today by the journal Science.

The report boost confidence that remdesivir, which is currently going through accelerated clinical trials at the University of Washington and other research centers across the country, will prove effective for treating COVID-19 patients. It also illustrates how a detailed picture of the coronavirus’ inner workings — provided through a technology known as cryogenic electron microscopy, or cryo-EM — can point to additional strategies for beating the virus.

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Protein puzzle game finds 99 ways to beat virus

Protein structure
This is one of the high-scoring protein designs that will be turned into an actual protein binder for testing as an coronavirus-blocking agent. (Stomjoh via Foldit / UW Institute for Protein Design)

Who would have thought a video game could identify potential treatments for COVID-19? Researchers at the University of Washington’s Institute for Protein Design certainly thought so, and so far the game has produced 99 chances to win.

The game is a protein-folding puzzler called Foldit, which was created at UW’s Center for Game Science more than a decade ago and has attracted nearly more than 750,000 registered players since then.

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Scientists get a fix on coronavirus’ deadly weapon

Coronavirus spike protein
These diagrams show the protein structure for the “spike” that’s used by the coronavirus known as COVID-19 to force its way into cells. The diagram at left shows the spike with a molecular key known as the RBD in the “down” position. The middle diagram shows the RBD-up conformation, and the diagram at right shows the spike on the SARS virus for comparison’s sake. (Wrapp, Wang et al. / UT-Austin / NIH via Science / AAAS)

Biochemists have created the first 3-D, atomic-scale map of key proteins in the killer coronavirus, opening up new possibilities for developing treatments and a vaccine.

Researchers at the University of Washington and its Institute for Protein Design are among the sleuths who’ll be taking advantage of the new clues.

The map shows the 3-D arrangement of proteins in the molecular “spike” that the virus known as COVID-19 uses to force its way into the cells that it infects. Once the virus gains entry, it delivers genetic code that takes control of the cells to spread the infection.

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A-Alpha Bio raises $2.8M for drug discovery

A-Alpha Bio team
The A-Alpha Bio team includes scientist Emily Engelhart, principal scientist David Colby, co-founder and CEO David Younger, co-founder and chief technology officer Randolph Lopez and engineering associate Charles Lin. (A-Alpha Bio Photo)

A Seattle startup that took root at the University of Washington has closed a $2.8 million seed round for a drug discovery platform that can sort through millions of protein interactions at once.

“We expect that we can go considerably further than that,” said David Younger, the co-founder and CEO of A-Alpha Bio.

A-Alpha Bio’s genetically engineered protein analysis technology, known as AlphaSeq, has the potential to speed up the process of evaluating drug candidates. That’s what attracted interest from investors including OS Fund, which led the seed round, plus AME Cloud Ventures, Boom Capital, Madrona Venture Group, Sahsen Ventures, Washington Research Foundation and a number of angel investors.

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Protein designers get a $45 million boost

David Baker and Neil King
University of Washington biochemists David Baker and Neil King show off molecular models of proteins at UW’s Institute for Protein Design. (UW IPD Photo / Ian Haydon)

The era of engineering proteins for medical applications just got a lot closer, thanks to a five-year, $45 million grant from The Audacious Project at TED to the Institute for Protein Design at the University of Washington School of Medicine.

The institute, headed by UW biochemist David Baker, is among eight recipients of Audacious grants announced today at the annual TED conference in Vancouver, B.C.

“We’re really thinking of this as a protein design revolution, parallel to the digital revolution at Bell Labs. … If you can design proteins exactly to order from first principles, you can solve a lot of problems that are facing humans today — primarily in medicine, but also in materials and energy,” Baker told GeekWire.

Among the potential products are a universal flu vaccinenon-addictive painkillers, smart proteins capable of identifying and treating cancer cells or the out-of-control cells that cause autoimmune disorders, potential treatments for neurodegenerative disorders and self-assembling proteins for solar cells or nanofabrication.

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