AI Article Synopsis
- - The text discusses pathogenic protozoa that cause severe conditions like blinding keratitis and encephalitis, highlighting a critical need for effective treatments.
- - It focuses on the enzyme sterol 14α-demethylase (CYP51), which plays a key role in the sterol biosynthesis of these pathogens, noting the enzyme's preference for certain substrates.
- - The study identifies strong inhibitors of CYP51, particularly the antifungal drug voriconazole and others, and provides crystal structures of CYP51 for future drug development aimed at combating amoebic infections.
Article Abstract
are free-living pathogenic protozoa that cause blinding keratitis, disseminated infection, and granulomatous amebic encephalitis, which is generally fatal. The development of efficient and safe drugs is a critical unmet need. sterol 14α-demethylase (CYP51) is an essential enzyme of the sterol biosynthetic pathway. Repurposing antifungal azoles for amoebic infections has been reported, but their inhibitory effects on CYP51 enzymatic activity have not been studied. Here, we report catalytic properties, inhibition, and structural characterization of CYP51 from . The enzyme displays a 100-fold substrate preference for obtusifoliol over lanosterol, supporting the plant-like cycloartenol-based pathway in the pathogen. The strongest inhibition was observed with voriconazole (1 h IC 0.45 μM), VT1598 (0.25 μM), and VT1161 (0.20 μM). The crystal structures of CYP51 with bound VT1161 (2.24 Å) and without an inhibitor (1.95 Å), presented here, can be used in the development of azole-based scaffolds to achieve optimal amoebicidal effectiveness.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11089504 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.4c00303 | DOI Listing |
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