In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ~6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds, and we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, Emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and 3-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, an FDA approved category B anthelmintic drug, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emphasized the urgency to develop effective therapeutics. Drug repurposing screening is regarded as one of the most practical and rapid approaches for the discovery of such therapeutics. The 3C-like protease (3CL pro ), or main protease (M pro ) of SARS-CoV-2 is a valid drug target as it is a specific viral enzyme and plays an essential role in viral replication. We performed a quantitative high-throughput screening (qHTS) of 10 755 compounds consisting of approved and investigational drugs, and bioactive compounds using a SARS-CoV-2 3CL pro assay. Twenty-three small molecule inhibitors of SARS-CoV-2 3CL pro have been identified with IC 50 s ranging from 0.26 to 28.85 μM. Walrycin B (IC 50 = 0.26 μM), hydroxocobalamin (IC 50 = 3.29 μM), suramin sodium (IC 50 = 6.5 μM), Z-DEVD-FMK (IC 50 = 6.81 μM), LLL-12 (IC 50 = 9.84 μM), and Z-FA-FMK (IC 50 = 11.39 μM) are the most potent 3CL pro inhibitors. The activity of the anti-SARS-CoV-2 viral infection was confirmed in 7 of 23 compounds using a SARS-CoV-2 cytopathic effect assay. The results demonstrated a set of SARS-CoV-2 3CL pro inhibitors that may have potential for further clinical evaluation as part of drug combination therapies to treating COVID-19 patients and as starting points for chemistry optimization for new drug development.

While vaccine development will hopefully quell the global pandemic of COVID-19 caused by SARS-CoV-2, small molecule drugs that can effectively control SARS-CoV-2 infection are urgently needed. Here, inhibitors of spike (S) mediated cell entry were identified in a high throughput screen of an approved drugs library with SARS-S and MERS-S pseudotyped particle entry assays. We discovered six compounds (cepharanthine, abemaciclib, osimertinib, trimipramine, colforsin, and ingenol) to be broad spectrum inhibitors for spike-mediated entry. This work could contribute to the development of effective treatments against the initial stage of viral infection and provide mechanistic information that might aid the design of new drug combinations for clinical trials for COVID-19 patients.