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The human body consists of over 30 trillion cells, and there’s a lot happening inside every cell. Just like the human body has organs that perform a specific function, cells have organelles that perform specific functions. Proteins help carry out those functions by moving things around, signaling, providing defense and more. Cells are constantly building and breaking down proteins.

“All proteins in our cells are constantly undergoing turnover,” Tom Bell, professor of chemistry, said. Bell’s research group specializes in medicinal chemistry and drug development.

Sometimes, proteins can be overexpressed or mutated due to a genetic or pathogenic condition, and cell function is disrupted. Graves’ Disease, for example, is an autoimmune disease caused by the production of too much of the thyroid hormone because of an antibody that activates the thyroid stimulating hormone receptor.

“In many diseases, the protein is either overexpressed, there's too much of it, or it's overactive, it's too sensitive,” Bell said. “You're trying to adjust this activity by decreasing its expression.”

In recent years, pharmaceutical companies have been making drugs that bind the protein of interest, causing a biochemical reaction that initiates the waste disposal system. These drugs take advantage of a natural cellular process happening in the proteasome, a cellular structure that serves as the protein waste factory. This process is called targeted protein degradation. Targeting a specific protein is important, because a drug that binds to other proteins can lead to side effects. Even for the target protein, it’s important not to wipe out the protein expression completely.

“Every protein has an important, useful function,” Bell said.

Bell’s research could pave a new path of drug development using compounds that get rid of faulty or excessive proteins in a different way. The new approach involves designing drug molecules called selective endoplasmic reticulum translocation inhibitors (SERTI). SERTIs selectively bind proteins while they are being made at the endoplasmic reticulum (ER) and trigger their degradation.

A large class of proteins are produced by weaving in and out of the membrane of the ER, like a needle and thread through a piece of fabric. The compounds being explored in Bell’s lab, called cyclotriazadisulfonamide (CADA) compounds, will prevent the protein from being threaded back into the membrane of the ER, leaving it exposed and susceptible to degradation.

A new direction

Bell began working with CADA compounds in the 1990s.

“I wasn’t doing any medicinal chemistry at the time,” Bell said. “We were trying to make a synthetic molecule that would bind lithium.”

At the same time, the AIDs crisis was wreaking havoc on the healthcare system. The National Cancer Institute was screening compounds to find a molecule that stood a chance against human immunodeficiency virus, or HIV. The institute requested that chemists send them compounds in case one was able to prevent the virus from replicating.

“We sent them about forty compounds, and this one compound, CADA, came up to be active against replication of HIV in cell cultures,” Bell said.

Bell worked with collaborators in Belgium to identify what made the compound effective, catalyzing his career shift to an entirely different area of research.

“We have a new way to do medicinal chemistry,” Bell said. “It’s been a joy in my life, because I never even took a course in biochemistry, and now I’m teaching medicinal chemistry.”

From research to development

Bell’s research since then has been largely dedicated to understanding which proteins the CADA compounds could act on, and which diseases could be treated using a drug based on CADA.

“Every time that we’ve chosen to investigate a protein related to a disease, we have found one of our compounds that works,” Bell said. “Different compounds are specific for different proteins, which is exactly what you want to see, that kind of selectivity.”

However, after nearly three decades, and despite the potential that the CADA compounds possess, there has been little effort made by pharmaceutical companies to exploit their potential.

Bell attributes the lack of attention paid to CADA compounds to the change in the model of how pharmaceutical companies operate. More often, pharmaceutical companies are buying startups that have already proven a drug to a great extent. This model doesn’t allow for much creativity or risk-taking at the pharmaceutical giants, Bell said.

“I think we're breaking through, and especially because now this protein degradation process is mainstream in the thinking of pharmaceutical researchers,” Bell said. “The key hurdle to overcome is to show that selective drugs can be developed using this approach. The dream is one protein, one drug.”

Bell said that every protein would need its own unique drug, and CADA-based drugs won’t treat every disease, but Bell hopes that they will get close to the selectivity provided by conventional drugs.

Bell’s lab has already shown potential for treating cancer, Graves’ disease, substance use disorder, preterm labor, malaria, and viral infections including COVID-19, hepatitis B, dengue and zika. For Bell, it’s hard to decide which proteins or diseases to investigate next.

“It’s like drinking from a firehose,” Bell said. “There are so many possibilities out there and I am eager for other people to get on this bandwagon, and it’s starting to happen.”

Bell recently began working with a startup company based in the Bay Area to develop SERTIs as practical drugs. Bell and his colleagues have submitted manuscripts for publication related to Grave’s Disease and cancer, the result of collaborations at the NIH and the University of Naples, respectively. He was selected to speak about this work at the Italian Society for Medicinal Chemistry conference in Rome in September.

Bell is working with Research Assistant Professor Scott Barnett and Regents and Foundation Professor Iain Buxton, both in the School of Medicine’s Department of Pharmacology to study pre-term labor, with a manuscript in the works. He is also collaborating with Subhash Verma, professor in the Department of Microbiology and Immunology, on COVID-19 and dengue fever. Bell is currently exploring rheumatoid arthritis and malaria with two graduate students in his group, Jaiden Christopher and Anabela Splitstoser, respectively. Bell’s group also consists of three undergraduate students, Martin Kerr, Gavin Paul and Aspen Easter, who are working on new methods to synthesize SERTIs. Another member of Bell’s group is Amarawan Intasiri, an analytical chemist who studies properties of experimental drugs including solubility, toxicity, cell permeability and metabolism.

“I owe all my success to my students and collaborators,” Bell said.