by Yan Su
The filamentous fungus Aspergillus fumigatus causes 600,000 deaths worldwide every year, primarily among immunocompromised individuals.
Inhibition of the fungus membrane enzyme CYP51B can prevent the growth of A. fumigatus. Voriconazole is currently the drug of choice, although the treatment efficiency is low and it causes adverse side effects that require therapeutic drug monitoring.
Galina I. Lepesheva, Ph.D., F. Peter Guengerich, Ph.D., and colleagues applied biochemical and X-ray crystallography methods to characterize binding of CYP51B to voriconazole and to an experimental inhibitor, VNI.
In a report published in the Journal of Biological Chemistry, they showed that the co-crystals of CYP51B-voriconazole and CYP51B-VNI had structural features in the active binding site that appeared to be fungal-specific, and different from human homologs of the enzyme.
The finding suggests the possibility of developing a highly efficient and specific inhibitor. The complex with VNI provides a structural and molecular basis for the design of a potentially novel drug to treat humans afflicted with filamentous fungal infections.
This research was supported by National Institutes of Health grant GM067871.
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