Mining a Kröhnke Pyridine Library for Anti-Arenavirus Activity.

Several arenaviruses cause hemorrhagic fever (HF) disease in humans and represent important public health problems in their en-demic regions. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus is a neglected human pathogen of clinical significance. There are no licensed arenavirus vaccines and current anti-arenavirus therapy is limited to an off-label use of ribavirin that is only partially effective. Therefore, there is an unmet need for novel therapeu-tics to combat human pathogenic arenaviruses, a task that will be facilitated by the identification of compounds with anti-arenaviral activity that could serve as probes to identify arenavirus-host interactions suitable for targeting, as well as lead com-pounds to develop future anti-arenaviral drugs. Screening of a combinatorial library of Krönhke pyridines identified compound KP-146 [(5-(5-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)-4'-methoxy-[1,1'-biphenyl]-3-yl)thiophene-2-carboxamide], as having strong anti-LCMV activity in cultured cells. KP-146 did not inhibit LCMV cell entry, but rather interfered with the activity of the LCMV ribonu-cleoprotein (vRNP) responsible for directing virus RNA replication and gene transcription, as well as with the budding process mediated by the LCMV matrix Z protein. LCMV variants with increased resistance to KP-146 did not emerge after serial passages in the presence of KP-146. Our findings support the consideration of Kröhnke pyridine scaffold as a valuable source to identify com-pounds that could serve as tools to dissect arenavirus-host interactions, as well as lead candidate structures to develop anti-arenaviral drugs.