Harringtonine: A more effective antagonist for Omicron variant

Area of Science:

• Virology
• Drug Discovery
• Molecular Biology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily infects host cells through membrane fusion.
• Identifying small-molecule antagonists that block this fusion process is crucial for developing new antiviral therapies.

Purpose of the Study:

• To develop a novel screening strategy for identifying SARS-CoV-2 membrane fusion inhibitors.
• To investigate the potential of harringtonine (HT) as a SARS-CoV-2 entry inhibitor.

Main Methods:

• Cell membrane chromatography (CMC) was employed to screen for small-molecule antagonists.
• Harringtonine's (HT) inhibitory effects on SARS-CoV-2 entry were assessed using various variants.
• The mechanism of action involved simultaneous targeting of the SARS-CoV-2 Spike protein and host TMPRSS2.

Main Results:

• Harringtonine (HT) demonstrated significant inhibitory activity against SARS-CoV-2 original strain, Delta, Omicron BA.1, and Omicron BA.5 variants.
• The half-maximal inhibitory concentration (IC50) values showed increasing potency against Omicron subvariants, with exceptionally low IC50 (<0.0019 μM) against Omicron BA.5.
• HT was confirmed to directly target both the SARS-CoV-2 Spike protein and the host cell surface TMPRSS2.

Conclusions:

• Harringtonine (HT) is a potent small-molecule antagonist effective against SARS-CoV-2 membrane fusion.
• HT's dual targeting of the viral Spike protein and host TMPRSS2 offers a promising therapeutic strategy against SARS-CoV-2, including highly transmissible variants.