Design and optimization of highly-selective fungal CYP51 inhibitors

Hoekstra, William J.; Garvey, Edward P.; Moore, William R.; Rafferty, Stephen W; Yates, Christopher M.; Schotzinger, Robert J.

doi:10.1016/j.bmcl.2014.05.068

Cited by 150 publications

(112 citation statements)

References 12 publications

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“…A much larger number of sensitive and resistant clinical isolates are required to fully characterize the in vitro antifungal activity of VT-1161. However, these data coupled with MIC data from other laboratories (16,17) and the biochemical data demonstrating nanomolar potency against the CYP51 target (17) indicate that VT-1161 is one of the most potent CYP51 inhibitors of C. albicans yet described.…”

Section: Discussionmentioning

confidence: 94%

“…NCT01891305 and NCT01891331, respectively; www.clinicaltrials.gov). It was rationally designed to be highly selective relative to human CYP enzymes while maintaining potent inhibition of the fungal CYP target (16,17). Its intrinsic in vitro antifungal potency against susceptible C. albicans was reproduced in this study where the MIC was at or below the lowest concentration tested of 0.015 g/ml.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of the Clinical Agent VT-1161 against Fluconazole-Sensitive and -Resistant Candida albicans in a Murine Model of Vaginal Candidiasis

Garvey

Hoekstra

Schotzinger

et al. 2015

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Efficacy of the Clinical Agent VT-1161 against Fluconazole-Sensitive and -Resistant Candida albicans in a Murine Model of Vaginal Candidiasis

Garvey

Hoekstra

Schotzinger

et al. 2015

Antimicrob Agents Chemother

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“…VT-1161 uses a 1-tetrazole to bind the heme iron within CYP51, which is critical in establishing greater selectivity for fungal CYP51 versus off-target human cytochrome P 450 (CYP) (13). We investigated the activity of VT-1161 against fungi that cause mucormycosis (Mucorales) in vitro and in vivo.…”

mentioning

confidence: 99%

VT-1161 Protects Immunosuppressed Mice from Rhizopus arrhizus var. arrhizus Infection

Gebremariam

Wiederhold

Fothergill

et al. 2015

Antimicrob Agents Chemother

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We studied the efficacy of the investigational drug VT-1161 against mucormycosis. VT-1161 had more potent in vitro activity against Rhizopus arrhizus var. arrhizus than against R. arrhizus var. delemar. VT-1161 treatment demonstrated dose-dependent plasma drug levels with prolonged survival time and lowered tissue fungal burden in immunosuppressed mice infected with R. arrhizus var. arrhizus and was as effective as high-dose liposomal amphotericin B treatment. These results support further development of VT-1161 against mucormycosis. Mucormycoses are infections afflicting the immunocompromised host and are occurring with increasing frequency (1-3). Risk factors for mucormycosis include a compromised immune status due to hematologic malignancies, neutropenia, steroid treatment, hyperglycemia, ketoacidosis and other forms of acidosis, deferoxamine therapy, and trauma (4-6). Despite disfiguring surgical debridement and adjunctive antifungal therapy, the overall mortality of mucormycosis remains at ϳ50% and can approach 100% in certain patient populations (2, 7-11). Clearly, new strategies to prevent and treat mucormycosis are urgently needed.VT-1161 is a novel, fungal-specific 14␣-lanosterol demethylase (CYP51) inhibitor with potent activity against yeasts and dermatophytes (12). VT-1161 uses a 1-tetrazole to bind the heme iron within CYP51, which is critical in establishing greater selectivity for fungal CYP51 versus off-target human cytochrome P 450 (CYP) (13). We investigated the activity of VT-1161 against fungi that cause mucormycosis (Mucorales) in vitro and in vivo. Because Rhizopus species are the most common Mucorales isolated from patients with mucormycosis (8,14,15), these studies focused on R. arrhizus var. arrhizus (also known as R. oryzae) and R. arrhizus var. delemar (also known as R. delemar) (16).The MIC (defined as the lowest concentration that causes 100% growth inhibition relative to the drug-free growth control) of VT-1161 was determined against seven clinical isolates of R. arrhizus var. arrhizus (lactic acid producers) and five clinical isolates of R. arrhizus var. delemar (fumaric acid producers) using the Clinical Laboratory and Standards Institute (CLSI) M38-A2 method (17). The VT-1161 median MICs were 0.5 g/ml (range, 0.25 to 2 g/ml) and Ͼ32 g/ml (range, 8 to Ͼ32 g/ml) against R. arrhizus var. arrhizus and R. arrhizus var. delemar isolates, respectively (Table 1).To evaluate the efficacy of VT-1161 in treating pulmonary mucormycosis, immunosuppressed mice were intratracheally infected with 2.5 ϫ 10 5 spores of R. arrhizus var. arrhizus 99-892 (a lung isolate with a VT-1161 MIC of 1.0 g/ml) after being sedated with ketamine and xylazine (18). Male ICR mice (23 to 25 g; Taconic Farms, Germantown, NY) were given irradiated feed and sterile water containing 50 g/ml enrofloxacin (Baytril; Bayer) ad libitum to control for bacterial infection. Neutropenia was induced by cyclophosphamide (200 mg/kg intraperitoneal) and cortisone acetate (500 mg/kg subcutaneous) on day Ϫ2 and ϩ3 relative to infect...

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“…Additionally, VT-1161 was rationally designed to selectively inhibit fungal CYP51 versus human CYPs (13,14), thus potentially reducing toxicity and drug-drug interactions. Azole antifungals, which target the same fungal CYP51 enzyme, are less selective and suffer from a range of toxicities directly related to the binding of human CYPs, including hepatotoxicity, drug-drug interactions due to induction or binding of liver microsome CYPs and other enzymes, limitations of metabolism, and some toxicities unique to the individual drugs (7,12,(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

“…VT-1161 is a novel fungal CYP51 inhibitor that was rationally designed through the use of a tetrazole moiety for greater selectivity against binding mammalian CYP enzymes while retaining the same or greater potency for the fungal CYP51 target (13). The potency of VT-1161 against Candida albicans CYP51 in a cellular assay was Յ0.5 nM compared to in vitro 50% inhibitory concentration (IC 50 ) values of ϳ100 M or greater against human CYP51 and key xenobiotic-metabolizing CYPs present in human liver microsomes (e.g., CYP2C9, 2C19, and 3A4) (14).…”

mentioning

confidence: 99%

Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models

Shubitz

Trinh

Galgiani

et al. 2015

Antimicrob Agents Chemother

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Design and optimization of highly-selective fungal CYP51 inhibitors

Cited by 150 publications

References 12 publications

Efficacy of the Clinical Agent VT-1161 against Fluconazole-Sensitive and -Resistant Candida albicans in a Murine Model of Vaginal Candidiasis

Efficacy of the Clinical Agent VT-1161 against Fluconazole-Sensitive and -Resistant Candida albicans in a Murine Model of Vaginal Candidiasis

VT-1161 Protects Immunosuppressed Mice from Rhizopus arrhizus var. arrhizus Infection

Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models

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