Author:
Warrilow A. G. S.,Hull C. M.,Parker J. E.,Garvey E. P.,Hoekstra W. J.,Moore W. R.,Schotzinger R. J.,Kelly D. E.,Kelly S. L.
Abstract
ABSTRACTThe binding and cytochrome P45051 (CYP51) inhibition properties of a novel antifungal compound, VT-1161, against purified recombinantCandida albicansCYP51 (ERG11) andHomo sapiensCYP51 were compared with those of clotrimazole, fluconazole, itraconazole, and voriconazole. VT-1161 produced a type II binding spectrum withCandida albicansCYP51, characteristic of heme iron coordination. The binding affinity of VT-1161 forCandida albicansCYP51 was high (dissociation constant [Kd], ≤39 nM) and similar to that of the pharmaceutical azole antifungals (Kd, ≤50 nM). In stark contrast, VT-1161 at concentrations up to 86 μM did not perturb the spectrum of recombinant human CYP51, whereas all the pharmaceutical azoles bound to human CYP51. In reconstitution assays, VT-1161 inhibitedCandida albicansCYP51 activity in a tight-binding fashion with a potency similar to that of the pharmaceutical azoles but failed to inhibit the human enzyme at the highest concentration tested (50 μM). In addition, VT-1161 (MIC = 0.002 μg ml−1) had a more pronounced fungal sterol disruption profile (increased levels of methylated sterols and decreased levels of ergosterol) than the known CYP51 inhibitor voriconazole (MIC = 0.004 μg ml−1). Furthermore, VT-1161 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. In summary, VT-1161 potently inhibitedCandida albicansCYP51 and culture growth but did not inhibit human CYP51, demonstrating a >2,000-fold selectivity. This degree of potency and selectivity strongly supports the potential utility of VT-1161 in the treatment ofCandidainfections.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
122 articles.
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