Development of Receptor-Integrated Magnetically Labeled Liposomes for Investigating SARS-CoV-2 Fusion Interactions

TL;DR

Scientists developed a new tool using magnetic sensors to study how SARS-CoV-2 fuses with cells, which could help in managing future outbreaks.

Contribution

A novel bioanalytical approach using magnetically labeled liposomes with ACE2 receptors to study SARS-CoV-2 fusion interactions.

Findings

The LION platform with ACE2 receptors can quickly quantify SARS-CoV-2 fusion interactions.

Molecular dynamics simulations show the spike protein's RBD interacts more favorably with ACE2 than with a lipid bilayer in the open conformation.

Environmental factors like calcium, cholesterol, pH, and temperature influence fusion processes.

Abstract

The impacts of highly pathogenic enveloped viruses, such
as SARS-CoV-2,
have turned scientific inquiry toward the fusion mechanisms responsible
for viral pathogenesis and to seek cost-effective and adaptable strategies
to mitigate future outbreaks. Current approaches for studying SARS-CoV-2
fusion include computational studies, pan-coronavirus viral inhibitors,
and modified peptides and lipopeptides, along with various nanotechniques.
Although these methodologies have illuminated the fusion mechanisms,
they possess key limitations that prevent their widespread utility
in outbreaks, including high financial or instrumental costs, operational
proficiency, cytotoxicity, or viral specificity. This work measures
changes in spin–spin T2 magnetic (transverse) relaxation
times using a benchtop NMR instrument and introduces a bioanalytical
approach to quickly quantify fusion interactions between the SARS-CoV-2
spike protein and liposome-coated iron oxide nanosensors (LIONs).
Additionally, this study modifies the LION platform by appending the
angiotensin-converting enzyme (ACE2) receptor, thereby creating LIONs-ACE2
that mimics the ACE2 host cell receptor targeted by SARS-CoV-2. Furthermore,
SARS-CoV-2 fusion to other receptors reported to be involved is also
examined. Environmental factors impacting fusion, such as calcium
ion concentration, cholesterol composition, pH, neutralizing antibodies,
and lower temperature, are investigated. Finally, molecular dynamics
(MD) simulation studies reveal that the receptor binding domain (RBD)
of the spike protein interacts more favorably with ACE2 than the lipid
bilayer in the opened conformation, yet the closed conformation of
RBD interacts with the bilayer with a similar energy as with ACE2.
These findings reveal how the LION platform offers a customizable,
fast-acting, inexpensive, and accessible mechanism for examining the
fusion process of SARS-CoV-2 and other enveloped viruses.

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