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
Centre for Cytochrome P450 Biodiversity, Institute of Life Science, College of Medicine, Swansea University, Swansea, Wales, United Kingdom.
Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
Antimicrob Agents Chemother. 2014 Dec;58(12):7121-7. doi: 10.1128/AAC.03707-14. Epub 2014 Sep 15.
The binding and cytochrome P45051 (CYP51) inhibition properties of a novel antifungal compound, VT-1161, against purified recombinant Candida albicans CYP51 (ERG11) and Homo sapiens CYP51 were compared with those of clotrimazole, fluconazole, itraconazole, and voriconazole. VT-1161 produced a type II binding spectrum with Candida albicans CYP51, characteristic of heme iron coordination. The binding affinity of VT-1161 for Candida albicans CYP51 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 inhibited Candida albicans CYP51 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 inhibited Candida albicans CYP51 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 of Candida infections.
将新型抗真菌化合物VT - 1161对纯化的重组白色念珠菌细胞色素P45051（CYP51，即ERG11）和人源CYP51的结合及抑制特性，与克霉唑、氟康唑、伊曲康唑和伏立康唑进行了比较。VT - 1161与白色念珠菌CYP51产生了II型结合光谱，这是血红素铁配位的特征。VT - 1161对白色念珠菌CYP51的结合亲和力很高（解离常数[Kd]≤39 nM），与唑类抗真菌药物的亲和力相似（Kd≤50 nM）。与之形成鲜明对比的是，浓度高达86 μM的VT - 1161并未干扰重组人CYP51的光谱，而所有的唑类药物均与人CYP51结合。在重组试验中，VT - 1161以紧密结合的方式抑制白色念珠菌CYP51的活性，其效力与唑类抗真菌药物相似，但在测试的最高浓度（50 μM）下未能抑制人源酶。此外，VT - 1161（MIC = 0.002 μg ml⁻¹）比已知的CYP51抑制剂伏立康唑（MIC = 0.004 μg ml⁻¹）具有更明显的真菌甾醇破坏特征（甲基化甾醇水平升高，麦角甾醇水平降低）。此外，VT - 1161对人CYP2C9、CYP2C19和CYP3A4有微弱抑制作用，表明其药物 - 药物相互作用潜力较低。总之，VT - 1161能有效抑制白色念珠菌CYP51及培养物生长，但不抑制人CYP51，显示出>2000倍的选择性。这种效力和选择性程度有力地支持了VT - 1161在治疗念珠菌感染方面的潜在效用。
