Structure-function relationship of Chikungunya nsP2 protease: A comparative study with papain.

Area of Science:

• Virology
• Biochemistry
• Structural Biology

Background:

• Chikungunya virus (CHIKV) is a significant mosquito-borne pathogen causing debilitating symptoms.
• CHIKV replication relies on the nsP2 protease, essential for processing viral polyproteins.
• The nsP2 protease's N-terminal segment shares structural identity with papain.

Purpose of the Study:

• To investigate the molecular mechanism of Chikungunya virus-nsP2 protease.
• To compare the nsP2 protease with papain using molecular dynamics simulations.
• To explore the potential of papain inhibitors as CHIKV therapeutics.

Main Methods:

• Molecular dynamics simulations were employed to analyze protease conformations.
• Induced fit docking was used to assess inhibitor binding to the nsP2 active site.
• Docking of CHIKV polyprotein peptides was performed to understand cleavage sites.

Main Results:

• CHIKV-nsP2 protease exhibits greater conformational flexibility than papain.
• Both proteases share an identical active site scaffold and catalytic diad.
• Non-peptide papain inhibitors showed potential binding to the nsP2 active site.

Conclusions:

• The conserved active site scaffold suggests a shared mechanism between nsP2 and papain.
• Papain inhibitors represent a promising avenue for developing novel Chikungunya virus treatments.
• Experimental validation of papain inhibitor efficacy against CHIKV-nsP2 is warranted.