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Antiviral drug discovery: Pyrimidine entry inhibitors for Zika and dengue viruses

Facundo N Gallo1, Agostina B Marquez2, Daniela M Fidalgo3

  • 1Centro de Investigaciones en Bionanociencias (CIBION) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Laboratorio de Estrategias Antivirales, CONICET, Instituto de Química Biológica (IQUIBICEN), Buenos Aires, Argentina.

European Journal of Medicinal Chemistry
|May 8, 2024
PubMed

Insights

New compound 16a shows potent antiviral activity against Dengue virus (DENV) and Zika virus (ZIKV). This discovery offers a promising avenue for developing new treatments against these significant mosquito-borne infectious diseases.

Area of Science:

  • Virology
  • Medicinal Chemistry
  • Public Health

Background:

  • Vector-borne diseases, including Dengue virus (DENV) and Zika virus (ZIKV), pose significant global health threats, particularly in tropical regions.
  • Current mosquito control methods are insufficient, and there are no specific antiviral drugs for DENV and ZIKV infections.
  • The viral envelope (E) protein is crucial for DENV and ZIKV cell entry, making it a key target for antiviral drug development.

Purpose of the Study:

  • To identify novel antiviral compounds targeting DENV and ZIKV with improved properties over existing pyrimidine analogs.
  • To design and synthesize molecules with enhanced selectivity and pharmacokinetic profiles for potential therapeutic applications against DENV and ZIKV.

Main Methods:

  • Low-throughput antiviral screening was employed to evaluate compound efficacy.
  • The study focused on identifying inhibitors targeting the DENV and ZIKV envelope (E) protein.
  • Pyrimidine analogs were synthesized and tested for their inhibitory activity.

Main Results:

  • Compound 16a emerged as a potent inhibitor of DENV-2 (EC50 = 1.4 μM) and ZIKV (EC50 = 2.4 μM).
  • Previous pyrimidine analogs (3e and 3h) showed inhibitory activity but were limited by poor water solubility.
  • The newly designed molecules aimed to overcome the limitations of earlier compounds.

Conclusions:

  • Compound 16a represents a promising lead for developing effective antiviral therapies against DENV and ZIKV.
  • Further optimization of compound selectivity and pharmacokinetics is crucial for advancing therapeutic potential.
  • This research contributes to the development of much-needed treatments for these widespread viral infections.
Keywords:
AntiviralsDENVEnvelope proteinPyrimidinesZIKV

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