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Related Experiment Video

Updated: Jun 9, 2026

High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
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Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors.

S Kaleem Ahmed1, Nicole N Haese2, Jaden T Cowan1

  • 1Drug Discovery Division, Southern Research, 2000 Ninth Avenue South, Birmingham, Alabama 35205, United States.

Journal of Medicinal Chemistry
|April 9, 2021
PubMed
Summary

Researchers identified a novel compound (1a) inhibiting Chikungunya virus (CHIKV). Further optimization yielded compound 8q with enhanced antiviral activity and stability, targeting viral and human enzymes.

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Area of Science:

  • Virology
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Chikungunya virus (CHIKV) poses a significant global health threat, necessitating the development of effective antiviral therapies.
  • Existing treatments for CHIKV are limited, highlighting the urgent need for novel therapeutic strategies.
  • Benzo[6]annulene derivatives have emerged as potential antiviral agents.

Purpose of the Study:

  • To identify and optimize novel inhibitors of Chikungunya virus (CHIKV).
  • To investigate the mechanism of action of identified CHIKV inhibitors.
  • To evaluate the in vivo efficacy of lead compounds in a CHIKV mouse model.

Main Methods:

  • High-throughput screening to identify initial CHIKV inhibitors.
  • Structure-activity relationship studies to optimize lead compounds.
  • In vitro antiviral assays (EC90, VTR, CC50) in human dermal fibroblast cells.
  • In vitro assays for liver microsomal stability.
  • Resistance mapping to identify CHIKV mutations.
  • Mechanism of action studies involving enzyme inhibition assays (dihydroorotate dehydrogenase).
  • In vivo CHIKV challenge mouse model.

Main Results:

  • Compound 1a, a benzo[6]annulene derivative, demonstrated CHIKV inhibition (EC90 = 1.45 μM) with no cytotoxicity (CC50 = 169 μM).
  • Optimization led to compound 8q with significantly improved cellular antiviral activity (EC90 = 270 nM) and enhanced liver microsomal stability.
  • CHIKV resistance to an analog (1c) was linked to a mutation in the nsP3 macrodomain.
  • Compounds were found to inhibit both CHIKV nsP3 macrodomain and human dihydroorotate dehydrogenase.
  • Compound 8q showed moderate efficacy in an in vivo CHIKV mouse model, with viral replication rescued via the pyrimidine salvage pathway.

Conclusions:

  • Novel benzo[6]annulene derivatives show potent antiviral activity against Chikungunya virus.
  • Compound 8q represents a promising lead candidate with improved potency, efficacy, and drug-like properties.
  • The dual mechanism of action, targeting viral and host factors, offers a potential strategy to overcome resistance.
  • Further investigation into modulating the pyrimidine salvage pathway may enhance in vivo efficacy.