Although a causal relationship between Zika virus (ZIKV) and microcephaly has been established, it remains unclear why ZIKV, but not other pathogenic flaviviruses, causes congenital defects. Here we show that when viruses are produced in mammalian cells, ZIKV, but not the closely related dengue virus (DENV) or West Nile virus (WNV), can efficiently infect key placental barrier cells that directly contact the fetal bloodstream. We show that AXL, a receptor tyrosine kinase, is the primary ZIKV entry cofactor on human umbilical vein endothelial cells (HUVECs), and that ZIKV uses AXL with much greater efficiency than does DENV or WNV. Consistent with this observation, only ZIKV, but not WNV or DENV, bound the AXL ligand Gas6. In comparison, when DENV and WNV were produced in insect cells, they also infected HUVECs in an AXLdependent manner. Our data suggest that ZIKV, when produced from mammalian cells, infects fetal endothelial cells much more efficiently than other pathogenic flaviviruses because it binds Gas6 more avidly, which in turn facilitates its interaction with AXL.Zika virus | Flaviviruses | AXL | placental barrier | fetal endothelial cell Z ika (ZIKV), West Nile (WNV), and dengue (DENV) viruses are closely related, and belong to the Flavivirus genus in the Flaviviridae family. Although a causal relation between ZIKV and microcephaly has been established by human and animal studies (1-7), it remains unclear why only ZIKV, but not other pathogenic flaviviruses, causes congenital diseases. Although WNV is known to infect neuronal cells and results in encephalitis (8), it does not cause microcephaly. DENV is not generally neurotropic and is not linked to congenital defects.To reach the fetal brain, a virus must be transported from the maternal to the fetal circulation, which necessitates crossing of the placental barrier. In the placenta, fetal blood in capillaries is separated from maternal blood by placental barrier cells, namely trophoblasts and fetal endothelial cells. Recent studies indicate that the placenta and its barrier cells are infected by ZIKV, and fetal brain lesions develop in mice, pigtail macaques, and humans (1-6, 9). However, it remains unclear why only ZIKV, and not other neurotropic flaviviruses, results in microcephaly and other congenital disorders.Although bona fide entry receptors for flaviviruses remain unknown, many cell surface-expressed molecules contribute to infection, including C-type lectins dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and DC-SIGN-related protein (L-SIGN) (10, 11) and phosphatidylserine (PS) receptors (12-15) . PS receptors, which serve as entry cofactors for flaviviruses, include members of the TIM (T-cell Ig mucin) family and the TAM (TYRO3, AXL, and MERTK) family. TIMfamily receptors bind PS directly (14, 15), whereas TAM-family members bind PS indirectly, through the soluble intermediates Gas6 (growth arrest-specific 6) and protein S present in serum and other bodily fluids (16, 17). Whereas Gas6 binds to all th...

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The main protease, M pro , of SARS-CoV-2 is an essential viral protein required for the earliest steps of infection. It is therefore an attractive target for antiviral drug development.

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LPCAT3 is an integral membrane acyltransferase in the Lands cycle responsible for generating C20:4 phospholipids and has been implicated in key biological processes such as intestinal lipid absorption, lipoprotein assembly, and ferroptosis. Small-molecule inhibitors of LPCAT3 have not yet been described and would offer complementary tools to genetic models of LPCAT3 loss, which causes neonatal lethality in mice. Here, we report the discovery by high-throughput screening of a class of potent, selective, and cell-active inhibitors of LPCAT3. We provide evidence that these compounds inhibit LPCAT3 in a biphasic manner, possibly reflecting differential activity at each subunit of the LPCAT3 homodimer. LPCAT3 inhibitors cause rapid rewiring of polyunsaturated phospholipids in human cells that mirrors the changes observed in LPCAT3-null cells. Notably, these changes include not only the suppression of C20:4 phospholipids but also corresponding increases in C22:4 phospholipids, providing a potential mechanistic explanation for the partial but incomplete protection from ferroptosis observed in cells with pharmacological or genetic disruption of LPCAT3.