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Updated: Jul 3, 2026
High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
High-throughput screening-based identification of paramyxovirus inhibitors
Jeong-Joong Yoon1, Dhruv Chawla, Tanja Paal
1Division of Pediatric Infectious Diseases, Department of Pediatrics, Emory Children's Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Abstract:
Several members of the paramyxovirus family constitute major human pathogens that, collectively, are responsible for major morbidity and mortality worldwide. In an effort to develop novel therapeutics against measles virus (MV), a prominent member of the paramyxovirus family, the authors report a high-throughput screening protocol that uses a nonrecombinant primary MV strain 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 < or =15.3 microM against the MV-Alaska strain and specificity indices ranging from 36 to >500. Library mining for structural analogs of several confirmed hits combined with retesting of identified candidates reveals a high accuracy of primary hit identification. Eleven of the confirmed hits interfere with viral entry, whereas the remaining 24 compounds target postentry steps of the viral life cycle. Activity testing against selected members of the paramyxovirus family reveals 3 patterns of activity: 1) exclusively MV-specific blockers, 2) inhibitors of MV and related viruses of the same genus, and 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.
Insights
Researchers screened 137,500 compounds to find new measles virus (MV) therapeutics. They identified 35 effective compounds, with some targeting viral entry and others post-entry steps, offering potential for broad-spectrum paramyxovirus inhibitors.
Area of Science:
- Virology
- Drug Discovery
- Infectious Diseases
Background:
- Paramyxoviruses are significant human pathogens causing widespread illness and death.
- Measles virus (MV) is a major paramyxovirus with substantial global health impact.
- Development of novel therapeutics against MV is crucial for public health.
Purpose of the Study:
- To establish a high-throughput screening protocol for identifying novel MV therapeutics.
- To discover small molecules that inhibit MV replication.
- To explore potential broad-spectrum paramyxovirus inhibitors.
Main Methods:
- A high-throughput screening assay utilizing a nonrecombinant primary MV strain.
- Screening of a 137,500-entry chemical library.
- Counterscreening, dose-response analysis, and structural analog mining.
Main Results:
- Identified 60 initial hit candidates, narrowed to 35 compounds with potent activity (<=15.3 microM) and high specificity indices (36 to >500).
- Eleven compounds inhibit MV viral entry; 24 target post-entry stages.
- Compounds showed varied activity profiles against other paramyxoviruses, including MV-specific, genus-specific, and broader-spectrum inhibitors.
Conclusions:
- The developed screening protocol is effective for identifying MV inhibitors.
- Identified compounds represent promising leads for MV-targeted therapies.
- Certain identified compounds may serve as starting points for developing broad-range paramyxovirus inhibitors.
