In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii

Hahn, Hye Jee; Escrig, Jose Ignacio; Shing, Brian; Debnath, Anjan

doi:10.3390/pathogens9090681

Cited by 5 publications

(3 citation statements)

References 46 publications

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“…We − and others − have explored the steroidogenic pathway in free-living amoebae and have pharmacologically validated several steroidogenic enzymes as drug targets. Inhibition of sterol 14-demethylase (CYP51) with a variety of FDA-approved CYP51 inhibitors (conazoles) induced massive autophagocytosis in cultured N.…”

Section: Introductionmentioning

confidence: 99%

Miconazole-like Scaffold is a Promising Lead for Naegleria fowleri-Specific CYP51 Inhibitors

Sharma,

Madia,

Tudino

et al. 2023

J. Med. Chem.

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Developing drugs for brain infection by Naegleria fowleri is an unmet medical need. We used a combination of cheminformatics, target-, and phenotypic-based drug discovery methods to identify inhibitors that target an essential N. fowleri enzyme, sterol 14-demethylase (NfCYP51). A total of 124 compounds preselected in silico were tested against N. fowleri . Nine primary hits with EC 50 ≤ 10 μM were phenotypically identified. Cocrystallization with NfCYP51 focused attention on one primary hit, miconazole-like compound 2a . The S -enantiomer of 2a produced a 1.74 Å cocrystal structure. A set of analogues was then synthesized and evaluated to confirm the superiority of the S -configuration over the R -configuration and the advantage of an ether linkage over an ester linkage. The two compounds, S - 8b and S - 9b , had an improved EC 50 and K D compared to 2a . Importantly, both were readily taken up into the brain. The brain-to-plasma distribution coefficient of S - 9b was 1.02 ± 0.12, suggesting further evaluation as a lead for primary amoebic meningoencephalitis.

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Section: Introductionmentioning

confidence: 99%

Miconazole-like Scaffold is a Promising Lead for Naegleria fowleri-Specific CYP51 Inhibitors

Sharma,

Madia,

Tudino

et al. 2023

J. Med. Chem.

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“…By inhibiting CYP51 with suitable drugs, fungi and protozoa lose their ability to produce C14-demethylated sterols, which causes cell membrane leakage and ultimately death of the pathogen. Accordingly, CYP51s are popular drug targets in pathogenic fungi and protozoa, including kinetoplastids and amoebae. − Acanthamoeba castellanii CYP51 (AcCYP51) is a pharmacologically validated drug target in A. castellanii; ,, however, the effectiveness of azole antifungal agents has been found to vary greatly …”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, CYP51s are popular drug targets in pathogenic fungi and protozoa, including kinetoplastids and amoebae. − Acanthamoeba castellanii CYP51 (AcCYP51) is a pharmacologically validated drug target in A. castellanii; ,, however, the effectiveness of azole antifungal agents has been found to vary greatly …”

Section: Introductionmentioning

confidence: 99%

Homodimerization Counteracts the Detrimental Effect of Nitrogenous Heme Ligands on the Enzymatic Activity of Acanthamoeba castellanii CYP51

et al. 2022

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Acanthamoeba castellanii is a free-living amoeba that can cause severe eye and brain infections in humans. At present, there is no uniformly effective treatment for any of these infections. However, sterol 14α-demethylases (CYP51s), heme-containing cytochrome P450 enzymes, are known to be validated drug targets in pathogenic fungi and protozoa. The catalytically active P450 form of CYP51 from A. castellanii (AcCYP51) is stabilized against conversion to the inactive P420 form by dimerization. In contrast, Naegleria fowleri CYP51 (NfCYP51) is monomeric in its active P450 and inactive P420 forms. For these two CYP51 enzymes, we have investigated the interplay between the enzyme activity and oligomerization state using steady-state and time-resolved UV–visible absorption spectroscopy. In both enzymes, the P450 → P420 transition is favored under reducing conditions. The transition is accelerated at higher pH, which excludes a protonated thiol as the proximal ligand in P420. Displacement of the proximal thiolate ligand is also promoted by adding exogenous nitrogenous ligands (N-ligands) such as imidazole, isavuconazole, and clotrimazole that bind at the opposite, distal heme side. In AcCYP51, the P450 → P420 transition is faster in the monomer than in the dimer, indicating that the dimeric assembly is critical for stabilizing thiolate coordination to the heme and thus for sustaining AcCYP51 activity. The spectroscopic experiments were complemented with size-exclusion chromatography and X-ray crystallography studies. Collectively, our results indicate that effective inactivation of the AcCYP51 function by azole drugs is due to synergistic interference with AcCYP51 dimerization and promoting irreversible displacement of the proximal heme–thiolate ligand.

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Anti-Acanthamoeba metallopharmaceuticals: Amoebicidal activity and synergistic effect of copper(II) coordination compound

da Silveira,

Cardoso,

Fernandes

et al. 2024

Biometals

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In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii

Cited by 5 publications

References 46 publications

Miconazole-like Scaffold is a Promising Lead for Naegleria fowleri-Specific CYP51 Inhibitors

Miconazole-like Scaffold is a Promising Lead for Naegleria fowleri-Specific CYP51 Inhibitors

Homodimerization Counteracts the Detrimental Effect of Nitrogenous Heme Ligands on the Enzymatic Activity of Acanthamoeba castellanii CYP51

Anti-Acanthamoeba metallopharmaceuticals: Amoebicidal activity and synergistic effect of copper(II) coordination compound

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