While targeted protein and RNA degradation are hot areas for R&D, the drugs developed so far come with limitations. Now, a new class with broader applications may not be far off.
In a study published April 26 in ACS Central Science, a research team led by scientists from the University of Cambridge described how they developed a new RNA-degrading small molecule they’ve dubbed a proximity-induced nucleic acid degrader, or PINAD. Their proof-of-concept drug, built to target the virus that causes COVID-19, successfully lowered the concentration of the virus in mice. The team plans to build more PINADs against other diseases, too.
“We are very keen to develop this technology further for COVID-19 as well as other RNA structures that are disease prevalent,” senior author Gonçalo Bernardes told Fierce Biotech Research in an email.
Pfizer, Boehringer Ingelheim, Ranok Therapeutics and many other firms have been working on small molecules that degrade target proteins, most notably in the form of proteolysis-targeting chimeras, or PROTACS. PROTACS use a cell’s own machinery to degrade target proteins, making them useful for “undruggable” diseases where a target protein either isn’t accessible or doesn’t have binding sites a small molecule can latch onto.
But going after proteins isn’t always the best strategy—or even possible. For instance, targeting proteins found on viruses can pressure them to mutate. And while some early studies have shown that targeted protein degradation can work against misfolded proteins like the ones found in Alzheimer’s disease, they have poorly-defined structures that are hard to home in on with small molecules.
In those cases, aiming at RNA is a better move. Ribonuclease targeting chimeras, or RIBOTACs, leverage chemical-induced proximity to degrade RNA by binding to both a target RNA and an enzyme called a ribonuclease. Still, they come with caveats too: They don’t work in cell types with low concentrations of ribonucleases, narrowing their applications.
With these limits in mind, the researchers set out to design a small molecule that could destroy targeted RNA just by being in close proximity to it, without requiring ribonucleases to do so. They used a spacer—a molecule that links two other molecules or structures—to connect a targeted RNA binding compound with a small molecule that cleaves RNA, also known as an RNA warhead. When the binding compound brings the RNA warhead close to the target RNA, it cuts it into pieces.
To put their PINAD to the test, the researchers turned to the virus that causes COVID-19: SARS-CoV-2. Using a mouse model with a particularly aggressive form of the disease, they found that while the drug didn’t confer a survival benefit, the mice did have lower viral loads in the lungs and reduced markers of inflammation. The drug was also well-tolerated.
The researchers plan to continue working on their COVID-19 PINAD and others to optimize their pharmacodynamic profile, with the hope that doing so could lead to a new class of antiviral drugs. They’re also making other tweaks that will make the drugs useful against other types of diseases, with a particular focus on making it capable of depleting RNA molecules that aren’t in high abundance or that have fast turnover rates, like messenger RNA (mRNA).
“Our technology has a lot of potential as it is very flexible and could be adaptive in terms of the target transcripts,” Bernardes said. “This is particularly relevant to contexts like cancer, neurodegeneration and autoimmune diseases.”