Mycolactone: A Broad Spectrum Multitarget Antiviral Active in the Picomolar Range for COVID-19 Prevention and Cure

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Mycolactone (MLN) is a toxin from Mycobacterium ulcerans.
• Previous studies indicated MLN binds to Munc18b, potentially inhibiting degranulation and exocytosis.
• The study explores MLN's interaction with endocytosis pathways and viral proteins.

Purpose of the Study:

• To investigate the effect of Mycolactone on endocytosis.
• To evaluate MLN's efficacy against SARS-CoV-2 and its variants.
• To assess MLN's potential as a therapeutic agent for COVID-19.

Main Methods:

• Computational analysis of MLN binding to proteins involved in endocytosis.
• In vitro SARS-CoV-2 live viral assays.
• Cytotoxicity assessments on human cell lines (A549, HEK293, Huh7.1).
• Antiviral activity testing against SARS-CoV-2 variants (alpha, delta, Omicron).

Main Results:

• MLN strongly binds to the N-terminal of clathrin and a novel SARS-CoV-2 fusion protein.
• 100% inhibition of SARS-CoV-2 at 60 nM and 84% inhibition at 30 nM.
• MLN demonstrated significantly higher potency than remdesivir and molnupiravir.
• High selectivity index (>65-fold) with low cytotoxicity against tested cell lines.
• Potent activity (<0.020 µM IC50) against alpha, delta, and Omicron variants.
• 100% inhibition of viral entry and spread at 134.6 nM.

Conclusions:

• MLN exhibits broad-spectrum antiviral activity against SARS-CoV-2 and its variants.
• MLN's mechanism involves binding to clathrin, a SARS-CoV-2 fusion protein, Sec61, and AT2R.
• MLN's potent efficacy and favorable safety profile suggest its potential as a therapeutic candidate for COVID-19 and other enveloped viruses.