Hantaviral therapeutics: life cycle targets and chemotherapeutic interventions

Orthohantaviruses represent a persistent global health threat, being responsible for life-threatening diseases such as Hemorrhagic Fever with Renal Syndrome (HFRS) and Hantavirus Cardiopulmonary Syndrome (HCPS). Despite high case fatality rates and recent outbreaks, there are currently no universally licensed antivirals or vaccines. Clinical management remains heavily reliant on supportive care and repurposed drugs, which often exhibit limited efficacy and dose-limiting toxicities. This review examines rational drug design strategies targeting critical steps in the viral life cycle, specifically Gn/Gc-mediated cellular entry and RNA-dependent RNA polymerase (RdRp)-driven genome replication. We evaluate the current landscape of viral inhibitors, including peptidomimetics, nucleoside analogues, and naturally derived compounds. To accelerate the discovery of novel treatments, we advocate for the integration of modern in silico screening to evaluate extensive chemical and natural product libraries. These broad compound collections offer a structurally diverse and largely untapped reservoir for antiviral development. Ultimately, expanding preclinical testing to include globally neglected variants will be essential to develop broad-spectrum hantaviral therapeutics capable of mitigating future epidemic threats.