Built to
Bind.
A first-in-class covalent heparanase inhibitor, designed to protect the kidney's filter. This is VL166 — caught in the act, inside the enzyme it shuts down.
Meet heparanase.
The enzyme that quietly dismantles the kidney's filter.
Heparanase trims heparan sulfate — the carbohydrate lining of the glomerular basement membrane, the kidney's delicate filtration barrier. In diabetic kidney disease its activity runs high, stripping that barrier, leaking protein, and triggering the inflammation and fibrosis that scar the kidney over time.
The fold here is a TIM barrel — eight strands wrapped in eight helices — paired with a smaller 8 kDa subunit. Down one face runs a long, positively charged groove. That groove is where the sugar binds.
Two glutamates, perfectly placed.
Every cut heparanase makes runs through two acidic residues facing each other across the groove. Glu225 is the acid/base. Glu343 is the nucleophile. Together they run a textbook retaining-glycosidase double-displacement — snip, then reset.
Catalytic, precise, and endlessly reusable — the very property that drives the damage in the kidney, and the property you must defeat to switch it off for good.
An unlikely hero: a sugar.
VL166 began with an unassuming molecule — the disaccharide.
Inspired by the enzyme's own substrate, AVIGI engineered a compact, mechanism-based inhibitor that drops into the −1 subsite where the real sugar would sit — and hides a strained epoxide warhead exactly where a bond would normally break. A trap, dressed up as breakfast.
The trap springs.
Keep scrolling — this is the whole trick, slowed right down.
Heparanase treats VL166 like substrate and begins to cut. Glu343 attacks the warhead's electrophilic carbon, C1 — but instead of releasing a product, the epoxide cracks open and the enzyme finds itself bonded to the inhibitor.
Glu225 plays its usual part, donating a proton to the opening ring. The reaction heparanase was built to catalyse becomes the reaction that disables it.
One bond. No way back.
What's left is a covalent ester between Glu343 and VL166 — the bright bond at the centre. The enzyme can't reset, can't release, can't cut. Inhibition is permanent.
That permanence is the point. A durable, upstream brake on the molecular driver of kidney damage — not another way to manage the symptoms.
Protect the filter.
In diabetic kidney disease, heparanase sits upstream of the damage. Silence it durably and the glomerular filtration barrier gets a chance to hold — less protein leak, less inflammation, less fibrosis.
VL166 is designed to slow, or prevent, the march toward end-stage renal disease. For millions of patients, a different kind of intervention — upstream, and built to last.
In Kidney Disease.
A spin-out of Leiden University ·
Leiden, The Netherlands
Structure · PDB 7PR7 — de Boer,
Armstrong, Lit, et al.,
PNAS 119 (2022)
Human heparanase in complex with VL166, 1.52 Å · Visualization by
AVIGI Therapeutics
An educational visualization. Atom positions for the bound complex are taken from the deposited 1.52 Å crystal structure; the reaction trajectory is a smooth interpolation between the resting inhibitor and the covalently bound end-state, so intermediate frames are illustrative rather than measured.