The ongoing COVID-19
pandemic has been brought on by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike glycoprotein
(S), which decorates the viral envelope forming a corona, is responsible
for the binding to the angiotensin-converting enzyme 2 (ACE2) receptor
and initiating the infection. In comparison to previous variants,
Omicron S presents additional binding sites as well as a more positive
surface charge. These changes hint at additional molecular targets
for interactions between virus and cell, such as the cell membrane
or proteoglycans on the cell surface. Herein, bottom-up assembled
synthetic SARS-CoV-2 miniviruses (MiniVs), with a lipid composition
similar to that of infectious particles, are implemented to study
and compare the binding properties of Omicron and Alpha variants.
Toward this end, a systematic functional screening is performed to
study the binding ability of Omicron and Alpha S proteins to ACE2-functionalized
and nonfunctionalized planar supported lipid bilayers. Moreover, giant
unilamellar vesicles are used as a cell membrane model to perform
competitive interaction assays of the two variants. Finally, two cell
lines with and without presentation of the ACE2 receptor are used
to confirm the binding properties of the Omicron and Alpha MiniVs
to the cellular membrane. Altogether, the results reveal a significantly
higher affinity of Omicron S toward both the lipid membrane and ACE2
receptor. The research presented here highlights the advantages of
creating and using bottom-up assembled SARS-CoV-2 viruses to understand
the impact of changes in the affinity of S for ACE2 in infection studies.