Thread by @ZdenekVrozina

May a new NIH preprint rewrite the COVID textbooks?
Turns out SARS-CoV-2 doesn’t start with ACE2. It latches onto heparan sulfate clusters on the cell surface. ACE2 only acts later, inside endosomes. Robust methods. Still preprint.🧵

https://twitter.com/atranscendedman/status/1966153647152312665

Why that matters - NIH labs have the time, tools, and independence to go deep. When they drop a preprint, it’s worth paying attention.

The tech here is next-level.
MINFLUX nanoscopy (1–3 nm precision)
STED super-resolution (60 nm)
electron microscopy
You can literally see individual virions docking.

What they saw surprised even them.
The virus doesn’t land on ACE2 at the cell surface.
It latches onto heparan sulfate (HS) clusters - tall sugar antennae that stick out far above the membrane.

These HS clusters aren’t random.
6 to 137 molecules each
Protrude up to 400 nm
About 1 per 6 micro m²
They form dense docking posts. Perfect for a virus looking to grab on.

ACE2, by comparison, barely pokes out of the membrane (10 nm). HS simply wins the race for first contact.

Once bound, the virus is swallowed into the cell by endocytosis.
Only inside the endosome does ACE2 take over - changing spike conformation, enabling fusion, releasing the viral genome.

So the new model is two-step.
HS clusters = the real docking receptor
ACE2 = downstream enabler
That flips the script on how we’ve thought about SARS-CoV-2 entry for 5 years.

And this isn’t just in petri dishes.
They tested it with the Omicron JN.1 variant in primary human airway cells (grown at air–liquid interface).
That’s as close as it gets to real lungs.

The results.
Block HS - virus can’t attach.
Block ACE2 - virus attaches fine, but infection stalls later.
It matches the two-step model perfectly.

They even tried pixantrone, a drug that binds HS.
It almost completely prevented JN.1 from sticking to and infecting airway cells.

This has big implications.
We’ve been targeting ACE2 and proteases.
But maybe the smarter move is blocking HS first.
Or even a combination - HS blockade up front, ACE2/protease blockade downstream.

And it’s not just about COVID.
HS is known to bind many viruses - HIV, Ebola, herpesviruses, papillomaviruses.
If HS clusters are a universal docking platform, then HS blockers could be a broad antiviral strategy.

Imagine a nasal spray that blocks HS binding. Cheap, broad, protective against multiple respiratory viruses.

Important - this is still a preprint (Sept 11, 2025).
No peer-review yet. Results need replication.
But if confirmed, this is a paradigm shift.
ACE2 isn’t the doorknob of the cell.
It’s the backroom lock.
The real doorknob is heparan sulfate.

Han at al., Nanoscopy Reveals Heparan Sulfate Clusters as Docking Sites for SARS-CoV-2 Attachment and Entry. biorxiv.org/content/10.110…