SARS-CoV-2 S Mutations: A Lesson from the Viral World to Understand How Human Furin Works

Area of Science:

• Virology
• Molecular Biology
• Evolutionary Biology

Background:

• Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a global pandemic.
• The virus's efficient human-to-human transmission is linked to its unique characteristics.
• Furin, a ubiquitous cellular protease, is crucial for the maturation of the SARS-CoV-2 spike (S) glycoprotein, enabling viral invasion and replication.

Purpose of the Study:

• To investigate the natural variations in the amino acid sequence around the S protein's cleavage site.
• To understand the evolutionary dynamics of SARS-CoV-2's interaction with Furin.
• To identify potential targets for antiviral drug development.

Main Methods:

• Analysis of naturally occurring amino acid variations in the S protein cleavage site.
• Assessment of gain-of-function phenotypes associated with specific mutations.
• Evaluation of synthetic surrogate cleavability.

Main Results:

• SARS-CoV-2 preferentially mutates at P positions, leading to single residue replacements.
• Observed mutations can result in gain-of-function phenotypes under certain conditions.
• Despite some mutations, the polybasic cleavage site and Furin dependence are maintained, with no observed escape variants.

Conclusions:

• SARS-CoV-2 exhibits rapid optimization of its S protein for Furin interaction.
• The virus's dependence on Furin remains consistent, highlighting its evolutionary strategy.
• Findings provide insights for developing drugs targeting Furin and Furin-dependent pathogens.