A New Frontier in Psychiatric Drug Discovery

Mahta Emrani | September 20, 2017

What are some of the most popular medications for the treatment of depression or anxiety? Prozac? Maybe Zoloft?

Noah Malmstadt is an associate professor in the Mork Family Department of Chemical Engineering and Materials Science. Photo credit/Michelle Henry

Let’s take Prozac for instance. Nearly three decades since its introduction to the market, this medication is still the most commonly prescribed for people suffering from depression. Same applies to Zoloft. While these drugs have been around long enough to make their way into the everyday vernacular, it is still not entirely clear why they work. Their long-term impacts on body and mind are also largely unknown.

When it comes to the treatment of various mental disorders, one thing is certain – progress has been slow. Perhaps too slow. The truth is, there have been very few, if any, significant developments in recent years.

However, change may be on the horizon.

Noah Malmstadt, a USC Viterbi associate professor in the Mork Family Department of Chemical Engineering and Materials Science, is one of the researchers exploring possible solutions for improving the existing drug discovery methods.

One of the barriers to the advancement of psychiatric drug discovery has been the challenge in testing new drugs. In psychopharmacology, there are no appropriate animal models for testing the impact and potency of new medications. This is in part due to the difficulty in characterizing complex cognitive disorders unique to human beings in non-human subjects.  Furthermore, no two cases are exactly the same. It is also difficult to predict the long-term side effects of certain treatments.

Up to now, the modus operandi has been to conduct tests on animal subjects. Others have been based on data mining (i.e., looking at existing records) and clinical trials or observations. While these methods are valid and valuable, they present limitations that slow the rate of drug discovery.

For the past three years, Malmstadt and his team, which includes Professor Richard W. Roberts, the Mork Department chair, and Malmstadt’s former Ph.D. student Mary Gertrude Gutierrez, “a driving force in the project,” have experimented with ways to construct artificial cells that could replicate complex biological behaviors. Their goal: find a new tool for drug discovery. “Instead of injecting the drug into an actual living being, we would inject it into an artificial cell to see what the interactions are going to be,” Malmstadt said.

To make this happen, the team had to find a way to work with notoriously hard to handle and very unstable membrane proteins. Particularly the Serotonin G protein coupled receptors, which are responsible for regulating mood and behaviors. Many antipsychotic medications target these proteins.

Associate Professor Noah Malmstadt, visiting undergraduate student Justin Peruzzi, and Mary Gertrude Gutierrez, PhD ’17 Photo courtesy of USC Viterbi

Malmstadt’s approach was to take these membrane proteins and transfer them from their native environment – the membrane of a living cell – into a completely artificial environment where they could maintain their natural properties and behave as they normally would. Once he could achieve this, these artificial cells would be the drug discovery tools that Malmstadt was looking for.

From existing research, Malmstadt knew that Diblock Copolymers are mechanically solid, highly stable, and much more resistant to permeation or destruction than lipid molecules. So he and his team began experimenting with Diblock Copolymers. To their surprise, the very fragile and hard to handle Serotonin proteins, once transferred into the more stable Diblock Copolymer environment, remained active.

This meant that the team could not only perform tests on these proteins while in an artificial environment, but it could also freeze dry and rehydrate them, which is very unusual for these highly unstable membrane proteins. This discovery was what Malmstadt was looking for. It was the litmus test that proved they could work with these very fragile and hard to handle proteins outside of their natural environments.

“We started working with the serotonin receptor because we have been working with it for a while and had generated a pretty large library of data on it,” Malmstadt said. “But what really motivated us to work on it was the implications for developing treatments for mental health.”

…what really motivated us to work on [the serotonin receptor] was the implications for developing treatments for mental health.Noah Malmstadt

As Roberts, who played an integral role in this research, explained: “G protein coupled receptors play a central role in the brain, in neurons, and in neurotransmission, which makes them important targets for new drugs that can alter and improve neuronal activity. A major challenge with these receptors is that they are very difficult to handle. Our new method helps solve this problem by creating synthetic membrane-like polymers that stabilize the proteins and thereby enable searching for new drugs.”

The team next hopes to build a more complex signaling pathway in these artificial cells, eventually adding genetic material to these cells.

“It is about understanding the minimum chemical constituent necessary to reproduce biological behaviors,” Malmstadt reflected.  “It could give us insight into what is necessary for the origins of life.”