Ebola virus infection can cause severe hemorrhagic fever with a high mortality in humans. The outbreaks of Ebola viruses in 2014 represented the most serious Ebola epidemics in history and greatly threatened public health worldwide. The development of additional effective anti-Ebola therapeutic agents is therefore quite urgent. In this study, via high throughput screening of Food and Drug Administration-approved drugs, we identified that teicoplanin, a glycopeptide antibiotic, potently prevents the entry of Ebola envelope pseudotyped viruses into the cytoplasm. Furthermore, teicoplanin also has an inhibitory effect on transcription-and replication-competent virus-like particles, with an IC 50 as low as 330 nM. Comparative analysis further demonstrated that teicoplanin is able to block the entry of Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) envelope pseudotyped viruses as well. Teicoplanin derivatives such as dalbavancin, oritavancin, and telavancin can also inhibit the entry of Ebola, MERS, and SARS viruses. Mechanistic studies showed that teicoplanin blocks Ebola virus entry by specifically inhibiting the activity of cathepsin L, opening a novel avenue for the development of additionalglycopeptidesaspotentialinhibitorsofcathepsinL-dependent viruses. Notably, given that teicoplanin has routinely been used in the clinic with low toxicity, our work provides a promising prospect for the prophylaxis and treatment of Ebola, MERS, and SARS virus infection.

Kidney fibrosis is the final common pathway of progressive kidney diseases, the underlying mechanisms of which is not fully understood. The purpose of the current study is to investigate a role of Piezo1, a mechanosensitive nonselective cation channel, in kidney fibrosis. In human fibrotic kidneys, Piezo1 protein expression was markedly upregulated. The abundance of Piezo1 protein in kidneys of mice with UUO or with folic-acid treatment was significantly increased. Inhibition of Piezo1 with GsMTx4 markedly ameliorated UUO or folic acid-induced kidney fibrosis. Mechanical stretch, compression or stiffness induced Piezo1 activation and pro-fibrotic responses in human HK2 cells and primary cultured mouse proximal tubular cells (mPTCs), which were greatly prevented by inhibition or silence of Piezo1. TGFβ-1 induced increased Piezo1 expression and pro-fibrotic phenotypic alterations in HK2 cells and mPTCs, which was again markedly prevented by inhibition of Piezo1. Activation of Piezo1 by Yoda1, a Piezo1 agonist, caused calcium influx and profibrotic responses in HK2 cells and induced calpain2 activation, followed by talin1 cleavage and upregulation of integrinβ1. Also, Yoda1 promoted the link between ECM and integrinβ1. In conclusion, Piezo1 is involved in the progression of kidney fibrosis and pro-fibrotic alterations in renal proximal tubular cells, likely through activating calcium-calpain2-integrinβ1 pathway.

Zika virus (ZIKV) is genetically and biologically related to other Flaviviridae family members and has disseminated to many countries. It is associated with severe consequences including the abnormal development of the neural system in fetuses and neurological diseases in adults. Therefore, developing anti-ZIKV drugs is of paramount importance. Screening of generic drugs revealed that several non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, naproxen, acetaminophen, and lornoxicam potently inhibit the entry of Zika-Env/HIV-1 pseudotyped viruses. They also significantly inhibited the replication of wildtype ZIKV, both in cell lines and in primary human fetal endothelial cells. Interestingly, NSAIDs exerted this inhibitory effect by potently reducing the expression of AXL, the entry cofactor of ZIKV. Further studies showed that NSAIDs down-regulated the PGE2/EP/cAMP/PKA signaling pathway, and reduced PKA-dependent CDC37 phosphorylation and the interaction between CDC37 and HSP90, which subsequently facilitated the CHIP/ubiquitination/proteasome-mediated AXL degradation. Taken together, our results highlight a new mechanism of action of antiviral agents, which may assist in designing a convenient strategy for treating ZIKV-infected patients. Zika virus (ZIKV) infection, which causes congenital malformations, including microcephaly and other neurological disorders, has attracted global attention. We observed that several NSAIDs significantly inhibited ZIKV infection. Based on our observations, we proposed a novel mechanism of action of antiviral compounds, which involves blockade of virus entry via degradation of the entry cofactor. Furthermore, NSAIDs can be practically used for preventing ZIKV infection in pregnant women, as certain NSAIDs, including ibuprofen and acetaminophen, are considered clinically safe.

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