Identification of small molecule inhibitors targeting the Zika virus envelope protein

Area of Science:

• Virology
• Drug Discovery
• Biochemistry

Background:

• Zika virus, a mosquito-borne flavivirus, causes severe neurological diseases like microcephaly and Guillain-Barré syndrome.
• No approved vaccines or antiviral therapies currently exist for Zika virus infection.
• The envelope (E) protein of Zika virus is a key target for antiviral development.

Purpose of the Study:

• To establish a novel assay for identifying small molecule inhibitors of Zika virus.
• To screen compound libraries for inhibitors targeting the Zika virus envelope protein.
• To characterize the antiviral activity and mechanism of identified inhibitors.

Main Methods:

• Development of a competitive amplified luminescent proximity homogeneous assay (ALPHAscreen).
• Screening of two compound libraries (nearly 27,000 compounds) using the ALPHAscreen assay.
• Characterization of lead compounds for antiviral activity, cytotoxicity, and mechanism of action (membrane fusion inhibition).

Main Results:

• Seven novel small molecule inhibitors targeting the Zika virus envelope protein were identified.
• All identified inhibitors demonstrated efficacy at non-cytotoxic concentrations.
• Compounds showed potent activity against dengue virus 2 but not vesicular stomatitis virus, suggesting a flavivirus-specific mechanism.

Conclusions:

• The developed ALPHAscreen assay is effective for discovering direct-acting antivirals against Zika virus.
• The identified compounds inhibit Zika virus by preventing E protein-mediated membrane fusion.
• This work provides a new strategy for developing antivirals targeting the envelope protein of Zika and other flaviviruses.