Crystal structure of the new investigational drug candidate VT-1598 in complex with Aspergillus fumigatus sterol 14{alpha}-demethylase provides insights into its broad-spectrum antifungal activity. [PublishAheadOfPrint]

Within the past decades, the incidence and complexity of human fungal infections have increased, and therefore the need for safer and more efficient, broad-spectrum antifungal agents is high. Herein, we characterize the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14α-demethylase (CYP51B) from the filamentous fungi Aspergillus fumigatus. VT-1598 displayed a high binding affinity to the enzyme in solution (with the K_d of 13±1 nM) and in the reconstituted enzymatic reaction revealed the inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/A. fumigatus CYP51 complex has been determined depicting the distinctive binding mode of the inhibitor in the enzyme active site and suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His-374, the CYP51 residue that is highly conserved across fungal pathogens and fungi-specific. Comparative structural analysis of A. fumigatus CYP51/voriconazole and C. albicans CYP51/VT-1161 complexes supports the role of H-bonding in fungal CYP51-inhibitor complexes, and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using two A. fumigatus strains (32820 and 1022) displayed direct correlation between the effects of the drugs on the CYP51B activity and fungal growth inhibition, indicating the noteworthy anti-A. fumigatus potency of VT-1598 and confirming its promise as a broad-spectrum antifungal agent.

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