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A high-throughput screen of preclinical, investigational and FDA-approved drugs identifies compounds that possess antiviral and neuroprotective effects against Zika virus infection in human neural progenitor cells and astrocytes. 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; 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 three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, 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.

Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drugs and 49 investigational drugs. The anti-SARS-CoV-2 activities of 230 of these confirmed compounds, of which 38 are approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA-approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set is a useful resource for drug repurposing efforts, including design of new drug combinations for clinical trials for SARS-CoV-2.

SARS-CoV-2 is the causative viral pathogen driving the COVID-19 pandemic that prompted an immediate global response to the development of vaccines and antiviral therapeutics. For antiviral therapeutics, drug repurposing allowed for rapid movement of existing clinical candidates and therapies into human clinical trials to be tested as COVID-19 therapies. One effective antiviral treatment strategy used early in symptom onset is to prevent viral entry. SARS-CoV-2 enters ACE2-expressing cells when the receptor-binding domain of the spike protein on the surface of SARS-CoV-2 binds to ACE2 followed by cleavage at two cut sites on the spike protein. TMPRSS2 has a protease domain capable of cleaving the two cut sites; therefore, a molecule capable of inhibiting the protease activity of TMPRSS2 could be a valuable antiviral therapy. Initially, we used a fluorogenic high-throughput screening assay for the biochemical screening of 6030 compounds in NCATS annotated libraries. Then, we developed an orthogonal biochemical assay that uses mass spectrometry detection of product formation to ensure that hits from the primary screen are not assay artifacts from the fluorescent detection of product formation. Finally, we assessed the hits from the biochemical screening in a cell-based SARS-CoV-2 pseudotyped particle entry assay. Of the six molecules advanced for further studies, two are approved drugs in Japan (camostat and nafamostat), two have entered clinical trials (PCI-27483 and otamixaban), while the other two molecules are peptidomimetic inhibitors of TMPRSS2 taken from the literature that have not advanced into clinical trials (compounds 92 and 114). This work demonstrates a suite of assays for the discovery and development of new inhibitors of TMPRSS2.

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 (3CLpro), or main protease (Mpro) 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 3CLpro assay. Twenty-three small molecule inhibitors of SARS-CoV-2 3CLpro have been identified with IC50s ranging from 0.26 to 28.85 μM. Walrycin B (IC50 = 0.26 μM), Hydroxocobalamin (IC50 = 3.29 μM), Suramin sodium (IC50 = 6.5 μM), Z-DEVD-FMK (IC50 = 6.81 μM), LLL-12 (IC50 = 9.84 μM), and Z-FA-FMK (IC50 = 11.39 μM) are the most potent 3CLpro inhibitors. The activities of 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 3CLpro 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. Competing Interest Statement The authors have declared no competing interest.

In the event of an outbreak due to an emerging pathogen, time is of the essence to contain or to mitigate the spread of the disease. Drug repositioning is one of the strategies that has the potential to deliver therapeutics relatively quickly. The SARS-CoV-2 pandemic has shown that integrating critical data resources to drive drug-repositioning studies, involving host-host, hostpathogen and drug-target interactions, remains a time-consuming effort that translates to a delay in the development and delivery of a life-saving therapy. Here, we describe a workflow we designed for a semi-automated integration of rapidly emerging datasets that can be generally adopted in a broad network pharmacology research setting. The workflow was used to construct a COVID-19 focused multimodal network that integrates 487 host-pathogen, 74,805 host-host protein and 1,265 drug-target interactions. The resultant Neo4j graph database named \"Neo4COVID19\" is accessible via a web interface and via API calls based on the Bolt protocol. We believe that our Neo4COVID19 database will be a valuable asset to the research community and will catalyze the discovery of therapeutics to fight COVID-19. https://neo4covid19.ncats.io.

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 two coronavirus spike proteins (S) were identified by screening a library of approved drugs with SARS-S and MERS-S pseudotyped particle entry assays. Using high-throughput screening technology, we discovered three compounds (cepharanthine, abemaciclib and trimipramine) to be broad spectrum inhibitors for spike-mediated entry. This work should contribute to the development of effective treatments against the initial stage of viral infection, thus reducing viral burden in COVID-19 patients. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://pubchem.ncbi.nlm.nih.gov/bioassay/1479145 * https://pubchem.ncbi.nlm.nih.gov/bioassay/1479150 * https://pubchem.ncbi.nlm.nih.gov/bioassay/1479149 * https://pubchem.ncbi.nlm.nih.gov/bioassay/1479147 * https://pubchem.ncbi.nlm.nih.gov/bioassay/1479148 * https://pubchem.ncbi.nlm.nih.gov/bioassay/1494158 * https://pubchem.ncbi.nlm.nih.gov/bioassay/1479144 * https://pubchem.ncbi.nlm.nih.gov/bioassay/1494157 * https://pubchem.ncbi.nlm.nih.gov/bioassay/1494156 * https://pubchem.ncbi.nlm.nih.gov/bioassay/1479146

Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://opendata.ncats.nih.gov/covid19/index.html

Effective visualization of complex synthesis routes is critical for computeraided synthesis planning (CASP), yet current solutions are limited in scope, integration flexibility, and chemical intuition. We introduce RouteWise, a versatile, containerized web application designed to address these unmet needs. Its modular architecture enables seamless integration into diverse environments, including popular prototyping platforms like Jupyter Notebook/Lab. Essentially, RouteWise adopts a reactioncentric visualization, prioritizing the intuitive representation of synthetic transformations over isolated substances, thereby enhancing usability for chemists. The platform accepts a well-defined, efficient JSON input representing synthesis graphs with routes defined as node cover sets, effortlessly incorporating reaction provenance, metadata (e.g., class, conditions), inventory information, and enabling simultaneous visualization of both evidencebased and predicted routes (e.g., from ASKCOS). Furthermore, RouteWise supports multiple parallel user sessions via a centralized FastAPI server, ensuring data privacy while facilitating automated data transmission from any CASP system. Scientific Contribution: This unique combination of features makes RouteWise the first tool to deliver accessible, chemically intuitive, and robust visualization for the evolving CASP landscape .

Identifying synthesis routes from knowledge graphs poses challenges beyond retrosynthesis, including path–finding artifacts and data issues. We introduce “SynGPS”, a novel algorithm that overcomes these limitations by identifying viable routes even with common artifacts. SynGPS can resolve nonsensical cycles, disconnect misleading links to starting materials, and remove ambiguous reactions, relying solely on topological heuristics for flexible scoring. We also present the Backtracking–Oriented Yield Aggregation (BOYA) algorithm, a new molar ratio–based method for calculating synthesis yield that addresses the molecular weight biases of existing weight-based approaches. Case studies demonstrate the effectiveness of SynGPS and BOYA algorithms, and we provide a rigorous theoretical framework that can facilitate the comparison of existing and future methods in the field of computer—aided synthesis planning (CASP).

The recent SmartGraph platform facilitates the execution of complex drug-discovery workflows with ease in the network-pharmacology paradigm. However, at the time of its publication, we identified the need for the development of an Application Programming Interface (API) that could promote biomedical data integration and hypothesis generation in an automated manner. This need was magnified at the time of the COVID-19 pandemic. This study addresses this hiatus. Most functionalities of the original platform were implemented in the SmartGraph API. We demonstrate that by using the API it is possible to transform the original semi-automated workflow behind the Neo4COVID19 database to a fully automated one. The availability of the SmartGraph API lends a significant improvement to the programmatic integration of networkpharmacology- oriented knowledge graphs and analytics, as well as predictive functionalities and workflows.