Structural and functional modelling of SARS-CoV-2 entry in animal models

Area of Science:

• Virology
• Molecular Biology
• Comparative Genomics

Background:

• The COVID-19 pandemic, caused by SARS-CoV-2, necessitates effective therapeutics.
• Research is hindered by a lack of suitable animal models for studying viral entry.
• Understanding host-pathogen interactions is crucial for developing treatments.

Purpose of the Study:

• To compare the usage of the ACE2 receptor and TMPRSS2/Furin proteases by the SARS-CoV-2 Spike glycoprotein across human and various animal models.
• To identify the most suitable animal models for studying SARS-CoV-2 entry and for developing targeted therapies.

Main Methods:

• Comparative sequence analysis of ACE2, TMPRSS2, and Furin.
• Molecular docking simulations of SARS-CoV and SARS-CoV-2 Spike proteins with ACE2.
• Computational analysis of binding modes and protein contacts.

Main Results:

• ACE2 shows significant sequence variability in the Spike protein interaction surface, influencing binding.
• SARS-CoV-2 Spike protein binds human ACE2 with high specificity.
• TMPRSS2 and Furin show less interspecies variability, not driving susceptibility differences.
• Macaque, ferrets, and hamsters are identified as promising models for studying Spike-ACE2 interactions.
• Transgenic models expressing human ACE2 are also suggested as valuable research tools.

Conclusions:

• Interspecies differences in ACE2 variability are critical for SARS-CoV-2 binding and host susceptibility.
• Macaques, ferrets, and hamsters are suitable animal models for SARS-CoV-2 research.
• Transgenic animal models expressing human ACE2 can aid in viral entry studies.