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Structural basis for antiviral inhibition of the main protease, 3C, from human enterovirus 93

Lionel Costenaro1, Zuzanna Kaczmarska, Carme Arnan

  • 1Institute for Research in Biomedicine, Barcelona, Spain.

Journal of Virology
|August 13, 2011
PubMed

Insights

This study determined the crystal structure of enterovirus B 3C protease (3C(pro)) and found that existing anti-rhinovirus drugs inhibit EV-93 replication, offering a basis for new antiviral therapies.

Area of Science:

  • Virology
  • Structural Biology
  • Drug Discovery

Background:

  • Enteroviruses (EVs) are common human pathogens causing diverse illnesses, from mild to severe neurological and cardiac conditions.
  • Current treatments and prophylaxis against most EVs are limited, highlighting the need for effective antiviral strategies.
  • The enterovirus 3C protease (3C(pro)) is crucial for viral replication and serves as a promising target for antiviral drug development due to its conserved substrate specificity.

Purpose of the Study:

  • To determine the crystal structure of 3C(pro) from enterovirus B, EV-93.
  • To evaluate the efficacy of known anti-rhinovirus (HRV) compounds against EV-93.
  • To provide a structural basis for developing broad-spectrum EV antiviral drugs.

Main Methods:

  • X-ray crystallography was used to determine the structure of EV-93 3C(pro) alone and complexed with compounds 1 (AG7404) and rupintrivir (AG7088).
  • In vitro assays were performed to assess the inhibition of EV-93 3C(pro) proteolytic activity.
  • Cell-based assays were conducted to evaluate the antiviral activity of the compounds against EV-93.

Main Results:

  • The crystal structure of EV-93 3C(pro) revealed a chymotrypsin-like fold with conserved features similar to other enterovirus proteases.
  • Both compound 1 and rupintrivir demonstrated activity against EV-93 in infected cells.
  • The compounds effectively inhibited the proteolytic activity of EV-93 3C(pro) in vitro.

Conclusions:

  • The structural and functional data provide a foundation for structure-guided drug design against EV-93.
  • Existing anti-HRV compounds show potential for treating EV infections, suggesting a possible broad-spectrum antiviral approach.
  • Further optimization of these compounds could lead to novel therapeutics for a wide range of enterovirus species.

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