Helicase

Helicases are a diverse class of essential molecular motor enzymes that utilize energy derived from ATP hydrolysis to separate or remodel nucleic acid duplexes. They are classified into six major superfamilies (SF1–SF6) and are integral to nearly every process involving DNA and RNA, including replication, repair, transcription, and translation initiation (e.g., eIF4A). In many diseases, specific helicases are either overexpressed to support rapid cellular proliferation or are essential for the replication of viral pathogens. Therapeutic interest in helicases has surged, particularly with the discovery of synthetic lethal relationships in oncology. For instance, the Werner syndrome helicase (WRN) has been identified as a critical target for tumors with microsatellite instability (MSI-H), leading to the clinical development of inhibitors like HRO761 and VVD-214 that induce lethal DNA damage in these specific cancer cells. Furthermore, helicase-primase inhibitors such as amenamevir have reached clinical approval for treating herpes simplex virus infections, highlighting the success of targeting this enzyme class in infectious diseases. Drug mechanisms vary widely, including allosteric locking of the enzyme in an inactive state and the interfacial trapping of helicases on DNA to create cytotoxic complexes.

Other names

DNA helicaseRNA helicaseNucleoside triphosphate-dependent helicaseMolecular motorSuperfamily 1-6 (SF1-SF6) helicase

Allosteric inhibition, ATP-competitive inhibition, Interfacial trapping of the enzyme on nucleic acids, and direct inhibition of nucleic acid unwinding activity.