Arenaviruses are a significant cause of hemorrhagic fever， an often-fatal disease for which there is no approved antiviral therapy. Lassa fever in particular generates high morbidity and mortality in West Africa， where the disease is endemic， and a recent outbreak in Nigeria was larger and more geographically diverse than usual. We are developing LHF-535， a small-molecule viral entry inhibitor that targets the arenavirus envelope glycoprotein， as a therapeutic candidate for Lassa fever and other hemorrhagic fevers of arenavirus origin. Using a lentiviral pseudotype infectivity assay， we determined that LHF-535 had sub-nanomolar potency against the viral envelope glycoproteins from all Lassa virus li... More
Arenaviruses are a significant cause of hemorrhagic fever， an often-fatal disease for which there is no approved antiviral therapy. Lassa fever in particular generates high morbidity and mortality in West Africa， where the disease is endemic， and a recent outbreak in Nigeria was larger and more geographically diverse than usual. We are developing LHF-535， a small-molecule viral entry inhibitor that targets the arenavirus envelope glycoprotein， as a therapeutic candidate for Lassa fever and other hemorrhagic fevers of arenavirus origin. Using a lentiviral pseudotype infectivity assay， we determined that LHF-535 had sub-nanomolar potency against the viral envelope glycoproteins from all Lassa virus lineages， with the exception of the glycoprotein from the LP strain from lineage I， which was 100-fold less sensitive than that of other strains. This reduced sensitivity was mediated by a unique amino acid substitution， V434I， in the transmembrane domain of the envelope glycoprotein GP2 subunit. This position corresponds to the attenuation determinant of Candid#1， a live-attenuated Junín virus vaccine strain used to prevent Argentine hemorrhagic fever. Using a virus-yield reduction assay， we determined that LHF-535 potently inhibited Junín virus， but not Candid#1， and the Candid#1 attenuation determinant， F427I， regulated this difference in sensitivity. We also demonstrated that a daily oral dose of LHF-535 at 10 mg/kg protected mice from a lethal dose of Tacaribe virus. Serial passage of Tacaribe virus in LHF-535-treated Vero cells yielded viruses that were resistant to LHF-535， and the majority of drug-resistant viruses exhibited attenuated pathogenesis. These findings provide a framework for the clinical development of LHF-535 as a broad-spectrum inhibitor of arenavirus entry and provide an important context for monitoring the emergence of drug-resistant viruses.
