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A critical bottleneck in drug discovery is identifying\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      models that accurately recapitulate human pathophysiology while remaining practical for high-throughput screening and medicinal chemistry efforts. Despite substantial preclinical activity, the paucity of clinically advanced\n                      <jats:italic toggle=\"yes\">Orthoflavivirus<\/jats:italic>\n                      (hereafter referred to as flaviviruses) antivirals underscores the need for improved discovery paradigms. Refinement of antiviral assays, informed by viral biology and guided by rigorous validation principles, will be central to identifying robust small-molecule inhibitors. 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