Helicases are enzymes that unravel DNA and RNA. They are essential for cellular survival, have been linked to a variety of malignancies and diseases, and are notoriously tough to target with medications.
New research now provides a powerful framework for developing covalent inhibitors that specifically target helicases. The report, published in the Journal of the American Chemical Society, outlines how researchers used this novel new platform to create compounds that target helicases found in COVID and certain malignancies.
“High-resolution structural and biochemical data alone are insufficient for identifying druggable sites in conformationally dynamic enzymes like helicases.” Our method can detect these spots while also providing chemical starting points for creating medicines that target helicases.”Mechanical challenges.
Helicases, which are complex molecular machineries that traverse DNA and RNA strands, must initiate the unraveling process that prepares genetic information for replication or transcription. However, when helicases go rogue, they can stimulate the growth of certain malignancies. Helicases play an important role in both viral replication and bacterial proliferation. As a result, certain medications that target these enzymes may be able to treat some tumors or halt infections altogether.
“Helicases are very hot targets right now,” says lead author Jared Ramsey, a graduate student in Kapoor’s lab. “Drugs that inhibit helicases are of great interest to the scientific community, and could be leveraged as new and effective treatments.”
Helicase inhibitors are, however, difficult to come by. Drug companies have occasionally discovered strategies for grinding one helicase or another to a standstill when testing thousands of tiny compounds, but these occurrences have proven to be uncommon. “The same was true in our lab,” Ramsey explains. “We were unable to identifiy helicase inhibitors using typical approaches such as high-throughput screening.”Ramsey, Kapoor, and colleagues wondered if electrophilic small molecules could be used to identify weak areas in a helicase, discreetly poking the enzyme for potential drug-binding sites. The concept of covalency is central to this idea, in which inhibitor candidates irreversibly attach to the helicase target, potentially avoiding difficulties caused by the enzymes’ dynamic and fluid natures. To that goal, the team chose two benign molecules and drove the so-called scout fragments toward a SARS-CoV-2 helicase.
Once they discovered potential binding locations on the helicase, they elevated the scouts to soldiers. “We just had to take a minimally elaborated electrophilic molecule, identify where it binds with mass spectrometry, and then use medicinal chemistry to modify it and screen a few versions of to achieve a potent, specific inhibitor,” Ramsey said.
The scientists also demonstrated that scout fragments could be tailored to shut down two specific helicases, BLM and WRN, which are linked to Bloom Syndrome and Werner Syndrome, respectively, as well as a variety of malignancies. While the presented findings are unlikely to translate into COVID or cancer treatments right away, they do provide a useful starting point for drug developers looking to create bespoke helicase targets.
“Our findings show how the platform we developed could accelerate work in other labs,” Ramsey said. “We use a basic science approach, and this is how many useful discoveries are made. This takes a difficult problem and offers us a good place to start.”