Recent advances in the medicinal chemistry of HSV-1 inhibitors (2020-2025): Emerging targets, modalities, and translational challenges.

Herpes simplex virus type 1 (HSV-1) causes widespread human infection, for which curative therapies remain unavailable. First-line TK-dependent nucleoside analogues such as acyclovir fail to eradicate latent virus and show limited activity against drug-resistant variants, highlighting an urgent unmet medical need. This review critically surveys HSV-1 inhibitor research published from 2020 to 2025, covering viral-targeted agents acting at entry, helicase-primase, metal-dependent processing enzymes and capsid-maturation steps, as well as host-directed candidates. We discuss structural foundations, mechanisms, structure-activity relationships, resistance risks and translational bottlenecks of representative compounds. Three priority directions for future anti-HSV-1 drug discovery are outlined: constructing inhibitors with high genetic-barrier against resistance, optimizing tissue-matched delivery for local or CNS indications, and advancing strategies targeting latent HSV-1 reservoirs.