Nonnucleoside inhibitor of measles virus RNA-dependent RNA polymerase complex activity

Area of Science:

• Virology
• Drug Discovery
• Molecular Biology

Background:

• Paramyxoviruses, including measles virus (MV), are significant human pathogens causing millions of cases and hundreds of thousands of deaths annually.
• Existing live-attenuated vaccines are effective, but novel antivirals are needed for severe cases and outbreak control.
• The emergence of resistance necessitates the development of MV inhibitors with diverse targets.

Purpose of the Study:

• To develop and implement a high-throughput screening assay for identifying novel measles virus antivirals.
• To discover and characterize new MV inhibitors with a distinct mechanism of action.
• To evaluate the potential of newly identified compounds as therapeutics against measles.

Main Methods:

• Development of a cell-based assay for high-throughput screening of measles virus (MV) antivirals.
• Secondary assays and chemical synthesis for hit confirmation and compound characterization.
• Mechanistic studies to elucidate the mode of action at a sub-infection level.

Main Results:

• A high-throughput screening assay yielded several hit candidates for MV antivirals.
• The most potent hit compound demonstrated high activity (35-145 nM) against diverse MV genotypes without affecting viral entry.
• This compound is a first-in-class nonnucleoside inhibitor of the MV RNA-dependent RNA polymerase complex, showing no cross-resistance with fusion inhibitors.

Conclusions:

• A novel, potent, and first-in-class nonnucleoside inhibitor of measles virus (MV) RNA-dependent RNA polymerase has been identified.
• This compound exhibits desirable drug-like properties and broad activity against circulating MV strains.
• The new compound class holds significant potential for therapeutic development against measles, alone or in combination with fusion inhibitors.