Taming cancer drugs with a molecular switch
Original story from the University of Washington School of Medicine (WA, USA).
In the lab, new molecular on/off controls helped tame a toxic cancer drug and sped up a coronavirus diagnostic test by more than 70-fold.
In a recent study, a new way to potentially control when drugs are active or inactive in the body has been introduced. The research showed that, instead of controlling how tightly proteins bind to partner molecules, scientists can now directly control how long they stay bound. This advance has broad implications for developing safer medicines.
“One way to control a medicine is through dose. We’ve added a second lever by designing molecules that can be switched off rapidly, even after they’ve taken full effect,” commented senior author David Baker, a professor of biochemistry at the University of Washington School of Medicine (UW Medicine; WA, USA).
Proteins often cling to other molecules to drive immune signaling, metabolism and more, but this stickiness can be problematic for medicines. For example, once an antibody drug begins to stimulate the immune system, it can be difficult to halt its activity if dangerous side effects emerge.
To address this concern, a team from the Baker Lab used computers to create custom proteins that latch onto target molecules. A separate molecule called an effector could then be added to force the bound complex into a strained configuration, causing it to fall apart.
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“In one experiment, interactions that would otherwise last for 20 minutes completely broke apart in just 10 seconds. I was so surprised by that speed-up that I had to repeat my measurements a few times before I could really believe it,” expressed author Adam Broerman, a chemical engineering PhD student training at the UW Medicine Institute for Protein Design.
His team applied this technology to interleukin-2 (IL-2), a powerful immune protein that has long been investigated as a cancer therapy but is notorious for toxic side effects. They created a switchable version of IL-2 that activates human immune cells in a lab dish and, with an added effector, silences them on demand.
This new form of control could make future cancer immunotherapies more tunable, thereby potentially protecting patients from runaway side effects, or allowing doctors to administer high-dose, short-duration treatments to achieve better cancer-killing results.
The same technique was used to create improved molecular sensors. In the study, a switch introduced into a light-emitting enzyme yielded a bright signal that could be toggled in seconds. This advance was adapted into a rapid coronavirus sensor that responds about 70 times faster than previous protein-based tests for SARS-CoV-2. The same approach might be used to create rapid sensors for disease markers, environmental pollutants and other chemicals.
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