Structure of the HRV-C 3C-Rupintrivir Complex Provides New Insights for Inhibitor Design

Area of Science:

• Virology
• Structural Biology
• Drug Discovery

Background:

• Human rhinoviruses (HRVs) are primary causes of the common cold.
• HRV-C species are linked to severe childhood illnesses and asthma exacerbations.
• 3C protease is crucial for viral replication and immune evasion, making it a significant drug target.

Purpose of the Study:

• To determine the structures of HRV-C15 3C protease in free and inhibitor-bound states.
• To understand the structural basis for drug specificity against HRV-C.
• To explore potential new therapeutic strategies based on 3C protease structure.

Main Methods:

• X-ray crystallography was used to obtain the three-dimensional structures.
• Analysis of the free and inhibitor-bound HRV-C15 3C protease structures.
• Comparison with other enterovirus 3C protease structures.

Main Results:

• The HRV-C15 3C protease exhibits a volume-decreased S1' subsite and a half-closed S2 subsite.
• The inhibitor rupintrivir adopted an intermediate conformation when bound to the protease.
• Structural similarities and differences with enterovirus 3C proteases were identified.

Conclusions:

• The unique structural features of HRV-C 3C protease offer insights into inhibitor design.
• The intermediate conformation of rupintrivir suggests new avenues for developing potent antiviral agents.
• Structural and sequence analysis points to potential repurposing of existing drugs for HRV-C infections.