High-Throughput Screening–Based Identification of Paramyxovirus Inhibitors
| Autor: | Richard K. Plemper, Serdar Kurtkaya, Jeong-Joong Yoon, Tanja Paal, Dhruv Chawla, James P. Snyder, Maina Ndungu, Yuhong Du, Aiming Sun |
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| Rok vydání: | 2008 |
| Předmět: |
High-throughput screening
Drug Evaluation Preclinical Transfection Antiviral Agents Biochemistry Article Analytical Chemistry Measles virus Automation Dogs Anti-Infective Agents Viral life cycle Viral entry Chlorocebus aethiops Animals Humans Paramyxovirinae Vero Cells biology Drug discovery biology.organism_classification Virology Models Chemical Drug Design Vero cell RNA Viral Molecular Medicine Identification (biology) Software Biotechnology |
| Zdroj: | SLAS Discovery. 13:591-608 |
| ISSN: | 2472-5552 |
| Popis: | Paramyxoviruses are negative strand non-segmented RNA viruses. Several members of this family constitute major human pathogens that, collectively, are responsible for major morbidity and mortality worldwide. In an effort to ultimately develop novel therapeutics against measles virus (MV), a prominent member of the paramyxovirus family, we report a high-throughput screening protocol that allows hit identification using non-recombinant primary MV strains as targets. Implementation of the assay has yielded 60 hit candidates from a 137,500-entry library. Counterscreening and generation of dose-response curves narrows this pool to 35 compounds with active concentrations ≤15.3 μM against the MV-Alaska strain and specificity indices ranging from 36 to >500. Library mining for structural analogs of several confirmed hits combined with re-testing of identified candidates reveals a low false-negative rate and, thus, a high accuracy of primary hit identification. Eleven of the confirmed hits were found to interfere with the viral entry machinery, while the remaining 24 compounds target post-entry steps of the viral life cycle. Activity testing against selected members of the paramyxovirus family reveals three patterns of activity: 1) exclusively MV-specific blockers; 2) inhibitors of MV and related viruses of the same genus; 3) broader-range inhibitors with activity against a different paramyxovirinae genus. Representatives of the last class may open avenues for the development of broad-range paramyxovirus inhibitors through hit-to-lead chemistry. |
| Databáze: | OpenAIRE |
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