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 E3 protein serves as a chemical tag that basically tells 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.
For example, molecular-glue medications could be administered to Alzheimer’s patients, to get rid of the misshapen tau proteins that are thought to play a role in causing the degenerative brain disease. Molecular glue could also give rise to protein-based treatments for cancer and autoimmune diseases, Younger said. One of the existing drugs that takes advantage of the concept is lenalidomide, also known as Revlimid, which is used in chemotherapy to get rid of tumor cells.
The problem is that it’s difficult to identify the right glue for the job.
“Just finding a small molecule that binds to a protein of interest is already a very, very hard problem,” Younger said. “In this case, you’re effectively doubling the challenge.”
Fortunately, A-Alpha Bio’s researchers have a lot of experience with that type of challenge. The main focus of their research has been a drug discovery platform called AlphaSeq that can sort through millions of protein interactions at once, to identify interactions with therapeutic effects.
Last year, the startup raised $2.8 million in seed funding to support the development of AlphaSeq, which uses yeast cells as a biochemical test bed for protein interactions on a grand scale.
The molecular-glue project aims to adapt AlphaSeq to identify molecular glues that are customized to latch onto proteins associated with a variety of diseases.
“What we have going for us at A-Alpha Bio is a game of numbers,” Younger said. “Humans have over 600 E3 ubiquitin ligases and huge numbers of potential target proteins that would be valuable to degrade.”
The traditional approach might be to take one given pair of proteins, and screen a million small molecules to see if any of them can glue the two proteins together. In contrast, AlphaSeq could screen hundreds of E3 ubiquitin ligases and hundreds of target proteins simultaneously.
“When we add in a small molecule, we’re not just looking for one E3 interacting with one target,” Younger explained. “We’re looking at any one of those hundreds of E3s interacting with any one of those hundreds of target proteins, effectively increasing our odds of finding something by multiple orders of magnitude.”
The two-year Phase II SBIR grant will help A-Alpha Bio fine-tune its AlphaSeq screening platform for finding molecular glues. “There are opportunities for some additional matching grants associated with Phase II grants, both from investment and from partnerships,” Younger said.
Could the right kind of glue gum up viral infections like COVID-19?
“There’s a possibility that it could work with viral protein, although I don’t know if it would be the most effective approach,” Younger said. “There are some other applications of the AlphaSeq platform that hopefully we’ll be able to talk about soon, and might be more applicable to COVID-19.”
Younger said A-Alpha Bio currently has the equivalent of six full-time employees, plus two job openings to fill, thanks to the seed round that was led by OS Fund as well as support from NSF, the University of Washington’s CoMotion lab and the Bill & Melinda Gates Foundation.
“We’re expecting to raise a Series A [round of funding] in 12 to 18 months, and I think you know part of that decision is based on the current economic climate,” Younger said. “We’re really fortunate to be able to do some really incredible science and actually continue to expand our team.”
Younger and Randolph Lopez, A-Alpha Bio’s chief technology officer, founded the venture in 2017 to commercialize the platform they invented while they were graduate researchers at UW. The startup’s collaborators include Seattle-based Lumen Biosciences and Massachusetts-based MassBiologics, as well as Olympic Protein Technologies and other partners the company isn’t yet ready to disclose. UW professors David Baker and Eric Klavins serve as A-Alpha Bio’s scientific advisers.