Helicase-primase inhibitors as next-generation anti-HSV agents: from current clinical status to structure-activity relationships and patent coverage

INTRODUCTION: Helicase-primase is an interesting target for small-molecule therapy of orthoherpesviruses in general and in particular herpes simplex virus (HSV) and varicella zoster virus (VZV) infections. With amenamevir already approved for the treatment of VZV and HSV in Japan and with pritelivir's granted breakthrough therapy designation and priority review for the treatment of acyclovir-resistant HSV infections in immunocompromised patients, other companies have also expressed interest in small-molecule helicase-primase inhibitors (HPIs). AREAS COVERED: We review the helicase-primase inhibitor landscape across HSV and VZV, focusing on patent coverage, key structure-activity relationships and the clinical progress of leading candidates. EXPERT OPINION: Following the clinical validation of the helicase-primase target by amenamevir and pritelivir, substantial patent activity has emerged around structurally diverse scaffolds aimed at enhancing target residence time, improving resistance profiles, enabling prolonged antiviral exposure and optimizing tissue distribution, including nerve penetration. In parallel, the availability of several cryo-electron microscopy structures of the helicase-primase complex has enabled structure-based and computer-aided drug design, facilitating the exploration of alternative scaffolds beyond the established chemotypes. The potential opportunities and limitations of the current HPIs, as well as the different dosage forms, are discussed.