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Updated: Apr 11, 2026
High-throughput Antiviral Assays to Screen for Inhibitors of Zika Virus Replication
Published on: October 30, 2021
The enterovirus 3C protease inhibitor SG85 efficiently blocks rhinovirus replication and is not cross-resistant with
Céline Lacroix1, Shyla George2, Pieter Leyssen1
1Laboratory for Virology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
Abstract:
The novel enterovirus protease inhibitor (PI) SG85 effectively inhibits the in vitro replication of 14 rhinoviruses representative of species A and B (median 50% effective concentration, 0.04 μM). A low-level SG85-resistant variant was selected that carried amino acid substitutions S127G and T143A in the 3C protease. Both substitutions are required for low-level resistance to SG85, as demonstrated by reverse genetics. Interestingly, there is no cross-resistance to SG85 and rupintrivir (another PI); a structural explanation is provided for this observation.
Insights
A new enterovirus protease inhibitor, SG85, effectively blocks rhinovirus replication in lab tests. Resistance requires two specific mutations in the 3C protease, showing no cross-resistance with other inhibitors.
Area of Science:
- Virology
- Drug Discovery
- Molecular Biology
Background:
- Enteroviruses, including rhinoviruses, are significant human pathogens.
- Developing effective antiviral therapies is crucial for managing enterovirus infections.
- Protease inhibitors (PIs) are a promising class of antiviral drugs.
Purpose of the Study:
- To evaluate the efficacy of the novel enterovirus protease inhibitor SG85.
- To investigate the mechanisms of resistance to SG85.
- To explore potential cross-resistance with other PIs.
Main Methods:
- In vitro replication assays were performed using 14 rhinovirus strains.
- Resistant variants were selected and characterized.
- Reverse genetics was employed to confirm the role of specific mutations.
- Structural analysis was conducted to understand drug-target interactions.
Main Results:
- SG85 demonstrated potent inhibition of rhinovirus replication (median EC50 = 0.04 μM).
- A low-level resistant variant emerged with dual amino acid substitutions (S127G and T143A) in the 3C protease.
- Both mutations were essential for SG85 resistance, confirmed by reverse genetics.
- No cross-resistance was observed between SG85 and rupintrivir.
Conclusions:
- SG85 is a highly effective inhibitor of diverse rhinovirus species.
- Resistance to SG85 is dependent on specific mutations in the 3C protease.
- The lack of cross-resistance suggests distinct binding mechanisms, offering therapeutic flexibility.
