High-Throughput Screening and Fragment-Based Approach for Flavivirus Antiviral Discovery

Members of the genus Orthoflavivirus pose severe global health threats with substantial morbidity and mortality. No specific antiviral therapies are currently approved, leaving clinical management limited to supportive care. The development of broad-spectrum pan-flavivirus antivirals requires targeting highly conserved structural and non-structural proteins essential for viral replication. High-throughput screening (HTS) and fragment-based drug discovery (FBDD) represent the primary complementary methodologies for initial hit identification. This review critically compares HTS and FBDD workflows, hit rates, target strategies, and overall efficacy in pan-flavivirus drug discovery.