Inspired by the role
of cell-surface glycoproteins as coreceptors
for pathogens, we report the development of
GlycoGrip
: a glycopolymer-based lateral flow assay for detecting SARS-CoV-2
and its variants.
GlycoGrip
utilizes glycopolymers
for primary capture and antispike antibodies labeled with gold nanoparticles
for signal-generating detection. A lock-step integration between experiment
and computation has enabled efficient optimization of
GlycoGrip
test strips which can selectively, sensitively, and rapidly detect
SARS-CoV-2 and its variants in biofluids. Employing the power of the
glycocalyx in a diagnostic assay has distinct advantages over conventional
immunoassays as glycopolymers can bind to antigens in a multivalent
capacity and are highly adaptable for mutated strains. As new variants
of SARS-CoV-2 are identified,
GlycoGrip
will serve
as a highly reconfigurable biosensor for their detection. Additionally,
via extensive ensemble-based docking simulations which incorporate
protein and glycan motion, we have elucidated important clues as to
how heparan sulfate and other glycocalyx components may bind the spike
glycoprotein during SARS-CoV-2 host-cell infection.
GlycoGrip
is a promising and generalizable alternative to costly, labor-intensive
RT-PCR, and we envision it will be broadly useful, including for rural
or low-income populations that are historically undertested and under-reported
in infection statistics.
The SARS-CoV-2 Omicron sub-lineage contains a significant number of mutations in the spike protein relative to earlier SARS-CoV-2 variants. Most notably, these mutations significantly increased the positive charge of the spike protein that is postulated to confer increased infectivity, potentially through enhanced interactions with cell surface receptors, and an altered host-cell entry mechanism. While heparan sulfate (HS) was shown to be a key co-receptor in the host-cell entry of SARS-CoV-2, the effect of spike charge on its interactions with heparan sulfate has not been clearly elucidated. Here, we investigate the role of evolving spike positive charge in accelerating long-range interactions to heparan sulfate and ACE2 in the glycocalyx. We show that the positively charged Omicron evolved enhanced binding rates to the negatively charged glycocalyx. Moreover, we discovered that while the Omicron spike-ACE2 affinity is comparable to Delta, the Omicron spike interactions with heparan sulfate are significantly enhanced, giving rise to a ternary complex of spike-HS-ACE2 with a larger proportion of double-bound and triple-bound ACE2. Our findings suggest that SARS-CoV-2 variants evolve to be more dependent on heparan sulfate in viral attachment and infection. We leveraged this understanding for the successful and sensitive detection of the Omicron variant. The evolving enhanced binding of SARS-Cov-2 to heparan sulfate presents new therapeutic and diagnostic opportunities.
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