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A key challenge is identifying compounds that are both efficacious and safe, as many candidates fail during development due to unforeseen toxicity. To address this, the embryonic zebrafish morphology, mortality, and behavior (ZBE) screen and the SYSTEMETRIC\u00ae Cell Health Screen (CHS) were employed to evaluate the safety of 403 compounds from the Cayman Antiviral Screening Library. Of these compounds, 114 were FDA-approved, 17 were discontinued, and 97 remained on the market. CHS identified 25% (104 compounds) as toxic, with a Cell Health Index\u2122 (CHI)\u2009&gt;\u20090.5. The embryonic zebrafish model identified an additional 20% as toxic (79), bringing the total to 183. ZBEscreen flagged 19 toxic hits among compounds still on the market, seven of which were also identified by CHS. The combined use of CHS and zebrafish models enhanced hazard detection. Together, CHS and ZBEscreen identified 45.5% of the library as potentially hazardous. Notably, the zebrafish non-hazardous compounds correlated strongly with over-the-counter or prescribed antiviral drugs, confirming their known safety profile. Over 130 hazard-associated compounds warranted further investigation. Using self-organizing maps, six distinct neighborhoods of compound similarity were identified. This dual approach streamlined the early detection of hazards associated with promising leads and is expected to facilitate faster, safer antiviral discovery.<\/jats:p>","DOI":"10.1007\/s00204-024-03948-3","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T17:51:54Z","timestamp":1735321914000},"page":"1029-1041","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Accelerating antiviral drug discovery: early hazard detection with a dual zebrafish and cell culture screen of a 403 compound library"],"prefix":"10.1007","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1751-4617","authenticated-orcid":false,"given":"Lisa","family":"Truong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew A.","family":"Bieberich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Raymond O.","family":"Fatig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7540-8236","authenticated-orcid":false,"given":"Bartek","family":"Rajwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Simonich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6190-3682","authenticated-orcid":false,"given":"Robyn L.","family":"Tanguay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,27]]},"reference":[{"issue":"1","key":"3948_CR1","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1021\/acsptsci.0c00174","volume":"4","author":"B Balasubramaniam","year":"2021","unstructured":"Balasubramaniam B, Prateek RS et al (2021) Antibacterial and antiviral functional materials: chemistry and biological activity toward tackling COVID-19-like pandemics. 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Andrew A. Bieberich and Raymond O. Fatig III declare that they are employees and shareholders of AsedaSciences, Inc. The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}