Christopher Hanson: Broad-Spectrum Platelet Inhibition via Non-Odorant OR2L13 Agonists
Christopher Hanson, Founder and CEO of Affinera Therapeutics, shared a post on LinkedIn:
“The receptor family that detects smells is turning up in tissues with no sensory role at all: kidney, prostate, heart muscle.
The newest one sits in platelets, and someone has now drugged it.
Platelets carry an olfactory receptor.
OR2L13 is the most abundant one in human platelets, cells that have no nucleus and no part in smell, and Scott Cameron’s lab at Cleveland Clinic has been working out what it does there since a 2022 paper that started from transcriptional profiling of platelets taken from aortic aneurysm patients.
Odorants activate the receptor. Carvone, from spearmint, is one of them, and none are usable as drugs, so the group screened 8,000 nonodorant compounds for OR2L13 agonists and characterized a probe called CCF0054500 in Circulation this year.
It inhibited platelet activation downstream of PAR1, P2Y12, glycoprotein VI and thromboxane receptors together, including in platelets drawn from coronary and peripheral artery disease patients who were still reactive on aspirin, clopidogrel or both. In a mouse arterial injury model thrombus formation fell by close to 90 percent with no lengthening of bleeding time.
The reported mechanism runs through phosphorylation of heat shock protein 27 and depolymerization of the actin cytoskeleton, leaving a platelet unable to spread into a stable clot whichever pathway triggered it.”
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