A broadly active flavivirus NS4B targeting compound that blocks NS4B-NS3 binding and replication organelle formation

SRI-38841 inhibits West Nile virus replication with an IC90 of 0.87 {micro}M and disrupts NS4B-NS3 binding and replication organelle formation in infected cells.

• Why it matters: Direct-acting antivirals that work across mosquito-borne orthoflaviviruses are lacking, and existing NS4B inhibitors have been largely DENV-specific.
• What they did: The study characterized SRI-38841 against WNV, DENV, ZIKV, and JEV, used serial passage and reverse genetics to validate NS4B resistance mutations, and applied docking to an AlphaFold2 NS4B model.
• The result: Resistance mapped to pocket residues A45 and K56, and SRI-38841 abolished replication organelle formation while retaining activity across all four viruses tested, unlike JNJ-A07 and NITD-688.

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