Late stages of the Zika virus life cycle are impaired by a selective TRPML2 agonist

The flavivirus genus includes human pathogenic viruses such as Dengue (DENV), West Nile (WNV) and Zika virus (ZIKV) posing a global health threat due to limited treatment options. Ion channels are crucial for various viral life cycle stages, but their potential as targets for antivirals is often not fully realized due to the lack of selective modulators. Here, we observe that the human endolysosomal cation channel TRPML2 agonist ML2-SA1 impairs the late life cycle stages of ZIKV, thus underscoring TRPML2 as a promising antiviral target. Upon treatment with ML2-SA1, levels of intracellular genomes and number of released virus particles of two different ZIKV isolates were significantly reduced. ML2-SA1-treated cells displayed enlarged vesicular structures and multivesicular bodies with ZIKV envelope protein accumulation. However, no increased ZIKV degradation in lysosomal compartments was observed. Rather, the antiviral effect of ML2-SA1 seemed to manifest by the compounds negative impact on genome replication. Moreover, ML2-SA1 treatment also led to intracellular cholesterol accumulation. ZIKV as well as many other viruses including the Orthohepevirus Hepatitis E virus (HEV) rely on the endolysosomal system and are affected by intracellular cholesterol levels to complete their life cycle. Since we observed ML2-SA1 to also negatively impact HEV infections in vitro, this compound may harbor a broader antiviral potential through perturbing the intracellular cholesterol distribution. Besides underscoring the potential of TRPML2 as a promising target for combatting viral infections, we uncover a tentative connection between this protein and cholesterol distribution within the context of infectious diseases.