Truong Lisa, Bieberich Andrew A, Fatig Raymond O, Rajwa Bartek, Simonich Michael T, Tanguay Robyn L
Department of Environmental and Molecular Toxicology, Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, OR, 97333, USA.
AsedaSciences Inc., West Lafayette, IN, USA.
Arch Toxicol. 2025 Mar;99(3):1029-1041. doi: 10.1007/s00204-024-03948-3. Epub 2024 Dec 27.
The constant emergence of new viral pathogens underscores the need for continually evolving, effective antiviral drugs. 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® 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™ (CHI) > 0.5. 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.
新病毒病原体的不断出现凸显了持续研发有效抗病毒药物的必要性。一个关键挑战是确定既有效又安全的化合物，因为许多候选药物在研发过程中因不可预见的毒性而失败。为解决这一问题，利用斑马鱼胚胎形态、死亡率和行为（ZBE）筛选以及SYSTEMETRIC®细胞健康筛选（CHS）来评估开曼抗病毒筛选库中403种化合物的安全性。在这些化合物中，114种已获美国食品药品监督管理局（FDA）批准，17种已停产，97种仍在市场上销售。CHS确定25%（104种化合物）有毒，细胞健康指数（CHI）>0.5。斑马鱼胚胎模型又确定了20%（79种）有毒，使有毒化合物总数达到183种。ZBE筛选在仍在市场上销售的化合物中标记出19种有毒化合物，其中7种也被CHS识别出来。CHS和斑马鱼模型的联合使用增强了危害检测能力。CHS和ZBE筛选共同确定该库中45.5%的化合物具有潜在危害性。值得注意的是，斑马鱼无毒化合物与非处方或处方抗病毒药物高度相关，证实了它们已知的安全概况。超过130种与危害相关的化合物值得进一步研究。利用自组织映射，确定了六个不同的化合物相似性邻域。这种双重方法简化了与有前景的先导化合物相关危害的早期检测，有望促进更快、更安全的抗病毒药物发现。
