Free tool streamlines ALS drug discovery with mass-spectrometry based model

Interested in finding a better way to develop drugs to treat amyotrophic lateral sclerosis (ALS), Northeastern researcher Jeffrey Agar and a team of scientists came up with a technique that improves the drug discovery workflow for an entire class of pharmaceuticals.

“This could now become the gold standard for how covalent drugs are developed from now on,” says Agar, an associate professor of chemistry and pharmaceutical sciences.

The goal is to make the technique free and available to labs small and large, part of what Agar refers to as the “democratization of science.”

“We decided not to patent this,” he says. “Just take it, use it and make drugs safer.”

There’s been a scientific explosion of interest in covalent drugs since the discovery of the antiviral Paxlovid. Covalent drugs form permanent bonds with target proteins, which makes them longer-lasting and potentially more potent than non-covalent drugs.

Some, like aspirin and penicillin, have been around for a while. But when it comes to a new generation of covalent drugs, limitations such as a large number of false positive “hits” during drug discovery and lack of methods to measure in vivo effect have slowed down the discovery process.

But Agar says he and a dozen colleagues—including Jared Auclair, Northeastern’s vice provost of Research Economic Development and director of Bioinnovation—have come up with a solution.

As described in Nature Communications, they developed a mathematical and bioanalytical model that uses mass spectrometry and protein analysis that allows researchers in even small labs to plug numbers into a “decision tree” to determine the potential efficacy of a drug under development.

“We try to keep it as simple as possible,” says Agar. “Now that we’ve done it, you don’t ever have to do it again. Take the number that you got and put it into this equation.”

Using a single drop of blood from the lab subject, the model measures how much of the drug is bound to the targeted protein, which yields far more information than just the presence of the drug, Agar says.

“Until we developed this, we couldn’t determine the dose regimen” that needed to be established in the second and third phase of clinical trials, says Agar.

Using the tree, researchers will be able to determine the drug’s concentration, potency and staying power—all important factors in deciding whether to continue to pursue development.

“If I gave a drug to you and it was gone within two minutes, I could pretty much be sure it would never work,” Agar says. “If I give it to you and it stays for an hour but it’s below a concentration where I know it will work, I know it will never be (an approved) drug.”

The technique “gives you a series of decisions that you can use to develop your own drug,” he says.

Among the drugs tested via the bioanalytical method and decision tree in the published research is the protein SOD1, a major antioxidant that when mutated is a common cause of the type of inherited ALS, including a prevalent mutation that often results in a patient’s death within a year of disease onset.

A novel treatment strategy pursued by Agar’s lab is to use a small molecule linker, S-XL6, to prevent SOD1 from mutating and splitting into pieces that form toxic clusters that grow with the progression of ALS.

“Along with the mass spectrometry, we had to derive and do the math and figure out the models for how to let people get a simple number on very complex data,” Agar says.

In addition to Auclair, the team included Novartis-supported Ph.D. student Rutali Brahme, as well as former graduate research assistant Amin Hossain, now a postdoctoral research fellow at Harvard Medical School.

“We’ve done this for ALS. And we made it possible to do with any drug,” Agar says.

The new technique will allow researchers to get better results from mouse clinical trials, Agar says. But at this point it would not eliminate the need for millions of dollars in funding to see clinical trials through the human subject stage, he says.

Potential ALS drugs developed at Northeastern that are helping lab animals live longer could still be five years away from being prescribed to patients, which is a sad state of affairs considering how the rare progressive disease robs people of the ability to talk, walk, chew and even breathe, Agar says.

But the newly developed bioanalytical and mathematical model and decision tree should definitely help labs large and small get through the early stages of drug discovery faster, Agar says.

“It’s the first set of tools for inside a living organism to find out what the body does to the drug and what the drug does to the body,” he says. “It’s all there, in one paper.”

This story is republished courtesy of Northeastern Global News news.northeastern.edu.