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

Tatiana Y Hargrove1, David C Lamb2, Zdzislaw Wawrzak3

  • 1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.

Journal of Medicinal Chemistry
|April 29, 2024
PubMed

Insights

Acanthamoeba infections require new drugs. Researchers studied Acanthamoeba sterol 14α-demethylase (CYP51) and found azole drugs like VT1161 show strong inhibition, aiding new treatment development.

Area of Science:

  • Biochemistry
  • Parasitology
  • Structural Biology

Background:

  • Acanthamoeba causes severe infections like keratitis and encephalitis.
  • Developing safe and effective drugs against Acanthamoeba is a critical need.
  • Antifungal azoles have been explored for amoebic infections, but their direct enzyme inhibition is unstudied.

Purpose of the Study:

  • To characterize the catalytic properties and inhibition of Acanthamoeba castellanii sterol 14α-demethylase (CYP51).
  • To determine the structural basis for inhibitor binding to A. castellanii CYP51.
  • To evaluate the potential of repurposed azoles as amoebicidal agents.

Main Methods:

  • Enzyme kinetics assays to determine substrate preference and inhibition constants.
  • Crystallography to obtain the structures of A. castellanii CYP51 with and without inhibitors.
  • Structure-based drug design principles.

Main Results:

  • A. castellanii CYP51 shows a 100-fold preference for obtusifoliol over lanosterol, indicating a plant-like sterol pathway.
  • Voriconazole, VT1598, and VT1161 demonstrated potent inhibition of CYP51 activity.
  • Crystal structures revealed inhibitor binding modes, providing a basis for scaffold development.

Conclusions:

  • Repurposed azoles, particularly VT1161, show significant promise for treating Acanthamoeba infections.
  • Structural insights into A. castellanii CYP51 facilitate the design of novel amoebicidal drugs.
  • Targeting CYP51 is a viable strategy for developing new therapies against blinding and fatal amoebic diseases.

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