2. Academic Validation
  3. Structure-Activity Relationship Studies Towards Analogues of Pleconaril as Novel Enterovirus-D68 Capsid-Targeting Antivirals

Structure-Activity Relationship Studies Towards Analogues of Pleconaril as Novel Enterovirus-D68 Capsid-Targeting Antivirals

  • bioRxiv. 2025 Aug 12:2025.08.08.668114. doi: 10.1101/2025.08.08.668114.
David L Cousins 1 2,  Ed J Griffen 1 2,  Jessica Stacey 1 2,  Alpha A Lee 3 2,  Yuliia Filimonova 4,  Anton Hlavin 4,  Yuliia Holota 4,  Roman Khmil 4,  Mykyta Kordubailo 4,  Oleksii Kostinov 4,  Dmytro Lesyk 4,  Ivan Logvinenko 4,  Mariia Lototska 4,  Viacheslav Lysenko 4,  Anna Pashchenko 4,  Mariia Pavlichenko 4,  Anzhela Rodnichenko 4,  Anton Tkachenko 4,  Brett L Hurst 5,  Justin G Julander 5,  Hong Wang 5,  Rebecca Pearl 6 2,  Jared Benjamin 6 2,  Randy Diaz-Tapia 6 2,  Mary E Gordon 6 2,  Randy A Albrecht 6 2,  Kris White 6 2
Affiliations

Affiliations

  • 1 MedChemica Consultancy Ltd, Macclesfield, Cheshire, SK11 6DU, UK.
  • 2 The ASAP Discovery Consortium.
  • 3 PostEra, 1 Broadway, 14th floor, Cambridge, MA 02142, USA.
  • 4 Enamine Ltd., Winston Churchill Street 78, Kyiv, 02094 Ukraine.
  • 5 Institute for Antiviral Research, Utah State University, Logan, UT 84322, USA.
  • 6 Department of Microbiology, Global Health and Emerging Pathogens Institute, Icahn, School of Medicine at Mount Sinai, New York, NY, USA.
PMID: 40832238 DOI: 10.1101/2025.08.08.668114
Abstract

Non-polio enteroviruses (NPEV) such as Enterovirus D68 (EV-D68) that are highly infectious and associated with polio-like neurological complications have caused outbreaks, globally, in recent years. While some clinical and preclinical compounds have shown efficacy against NPEV in-vitro, liabilities that caused historical compounds such as pleconaril to fall short of FDA approval still remain. We present herein SAR and SPR studies of analogues of clinical compounds such as pleconaril and vapendavir against EV-D68 as a representative NPEV. Numerous structurally differentiated analogues with EV-D68 Antiviral activity and useful ADME properties were discovered, which could serve as starting points for future EV drug discovery campaigns. Screening against a panel of enteroviruses revealed moderately broad-spectrum anti-EV activity of compound 26.

Keywords

Antiviral; Capsid; Drug Discovery; EV-D68; Enterovirus; Hit To Lead; Pandemic Preparedness; Pleconaril; Vapendavir.

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