Discovery of first-in-class human glycolate oxidase near infrared molecular rotor inhibitors (NIRGOi)

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Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that affects the metabolism of oxalate leading to formation of renal calculi and end stage kidney failure. Currently, no specific drug exists for PH1 treatment, while human glycolate oxidase (hGO), which influences endogenous oxalate synthesis, is a clinically validated target for PH1 treatment. We envisioned the possibility of exploiting the reported salicylate scaffold as an hGO interactor to develop the first in their class Near Infrared hGO inhibitors, that we termed NIRGOi. These could enable the simultaneous tracking and inhibition of hGO in a single moiety. We encompassed different electron acceptors (A) and 5-formylsalicylic acid, the electron donor (D), as a two in one moiety, to develop three D-A-type NIRGOi, new compounds capable of enhancing their photophysical properties upon interaction with the target protein, hGO. Their photophysical properties verified that the D-A interactions successfully redshifted the emission maxima to wavelengths ranging from 550 nm to 690 nm. Their interaction with hGO was first modelled in silico and then an array of in vitro assays were used to verify their low micromolar efficacy along with the alteration of their photophysical properties upon binding. This study provides new tools, the NIRGOi, that are promising starting points for the development of NIR reporting probes to explore and potentially treat Primary Hyperoxaluria type 1.

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