Identification of Potent and Selective Inhibitors of Acanthamoeba: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target

Hargrove, Tatiana Y.; Lamb, David C.; Wawrzak, Zdzislaw; Hull, Marcus; Kelly, Steven L.; Guengerich, F. Peter; Lepesheva, Galina I.

doi:10.1021/acs.jmedchem.4c00303

Identification of Potent and Selective Inhibitors of Acanthamoeba: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target

Journal Article · Mon Apr 29 00:00:00 EDT 2024 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.4c00303· OSTI ID:2470115

Hargrove, Tatiana Y. ^[1]; Lamb, David C. ^[2]; Wawrzak, Zdzislaw ^[3]; Hull, Marcus ^[2]; Kelly, Steven L. ^[2]; ^[1]; ^[1]

Vanderbilt Univ., Nashville, TN (United States). School of Medicine
Swansea University (United Kingdom)
Northwestern Univ., Argonne, IL (United States). Synchrotron Research Center

Acanthamoeba 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. Acanthamoeba 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 Acanthamoeba CYP51 enzymatic activity have not been studied. Here, we report catalytic properties, inhibition, and structural characterization of CYP51 from Acanthamoeba castellanii. 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 IC₅₀ 0.45 μM), VT1598 (0.25 μM), and VT1161 (0.20 μM). The crystal structures of A. castellanii 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470115

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 9 Vol. 67; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Identification of Potent and Selective Inhibitors of Acanthamoeba: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target

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