Researchers forge new path to combat viruses and cancers with helicase inhibitors

"High-resolution structural and biochemical data alone are not sufficient for finding druggable sites in conformationaly dynamic enzymes such as helicases. Our approach can identify these sites and also provide chemical starting points for developing drugs that target helicases."

Mechanical difficulties 

Complex molecular machines that traverse DNA and RNA strands, helicases must kickstart the unraveling process that prepares genetic information for processes such as replication or transcription. But when helicases go rogue, they can promote the growth of some cancers. At the same time, helicases are also crucial for viral replication and bacterial proliferation. It follows that different drugs targeting these enzymes could treat certain cancers, or stop infections in their tracks.

Ramsey, Kapoor, and colleagues wondered whether electrophilic small molecules could be used to scout out the weak points in a helicase, quietly prodding the enzyme for potential binding sites susceptible to drugs. Central to this idea is the concept of covalency, where inhibitor candidates irreversibly bind the helicase target, possibly circumventing complications from the dynamic and fluid nature of these enzymes. To that end, the team selected two innocuous molecules and directed the so-called scout fragments toward a helicase of SARS-CoV-2.

"Our findings show how the platform we developed could accelerate work in other labs," Ramsey says. "We take a basic science approach, and that's how many useful findings are uncovered. This takes a challenging problem and gives us a solid place to start."

Source:Journal reference:

Ramsey, J. J., et al. (2023). Using a Function-First “Scout Fragment”-Based Approach to Develop Allosteric Covalent Inhibitors of Conformationally Dynamic Helicase Mechanoenzymes. Journal of the American Chemical Society. doi.org/10.1021/jacs.3c10581.