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57. Novel Antifungal Drug Discovery Based on Targeting Pathways Regulating the Fungus-Conserved Upc2 Transcription Factor

Author

Gallo-Ebert, Christina, Donigan, Melissa, Stroke, Ilana L., Swanson, Robert N., Manners, Melissa T., Francisco, Jamie, Toner, Geoffrey, Gallagher, Denise, Huang, Chia-Yu, Gygax, Scott E., Webb, Maria, and Nickels, Joseph T.

Abstract

ABSTRACTInfections by Candida albicansand related fungal pathogens pose a serious health problem for immunocompromised patients. Azole drugs, the most common agents used to combat infections, target the sterol biosynthetic pathway. Adaptation to azole therapy develops as drug-stressed cells compensate by upregulating several genes in the pathway, a process mediated in part by the Upc2 transcription factor. We have implemented a cell-based high-throughput screen to identify small-molecule inhibitors of Upc2-dependent induction of sterol gene expression in response to azole drug treatment. The assay is designed to identify not only Upc2 DNA binding inhibitors but also compounds impeding the activation of gene expression by Upc2. An AlphaScreen assay was developed to determine whether the compounds identified interact directly with Upc2 and inhibit DNA binding. Three compounds identified by the cell-based assay inhibited Upc2 protein level and UPC2-LacZgene expression in response to a block in sterol biosynthesis. The compounds were growth inhibitory and attenuated antifungal-induced sterol gene expression in vivo. They did so by reducing the level of Upc2 protein and Upc2 DNA binding in the presence of drug. The mechanism by which the compounds restrict Upc2 DNA binding is not through a direct interaction, as demonstrated by a lack of DNA binding inhibitory activity using the AlphaScreen assay. Rather, they likely inhibit a novel pathway activating Upc2 in response to a block in sterol biosynthesis. We suggest that the compounds identified represent potential precursors for the synthesis of novel antifungal drugs.

Published
2013
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58. SEX DIFFERENCES IN PLASMA PROTEOMICS AND ASSOCIATED CLINICAL OUTCOMES IN HEART FAILURE WITH REDUCED EJECTION FRACTION.

Author

Carland, Corinne, Azzo, Joe David, Zhao, Lei, Liu, Laura, Gunawardhana, Kushan, Ebert, Christina, Zamani, Payman, Van Empel, Vanessa, Richards, Mark, Rietzschel, Ernst R., Javaheri, Ali, Mann, Douglas L., Cappola, Thomas P., and Chirinos, Julio A.

Subjects
*VENTRICULAR ejection fraction, *HEART failure, *TREATMENT effectiveness, *PROTEOMICS
Published
2024
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59. Urinary Proteomics and Outcomes in Heart Failure With Preserved Ejection Fraction.

Author

Carland C, Zhao L, Salman O, Cohen JB, Zamani P, Xiao Q, Dongre A, Wang Z, Ebert C, Greenawalt D, van Empel V, Richards AM, Doughty RN, Rietzschel E, Javaheri A, Wang Y, Schafer PH, Hersey S, Carayannopoulos LN, Seiffert D, Chang CP, Gordon DA, Ramirez-Valle F, Mann DL, Cappola TP, and Chirinos JA

Subjects
Humans, Male, Female, Aged, Middle Aged, Prognosis, Mineralocorticoid Receptor Antagonists therapeutic use, Ventricular Function, Left, Risk Factors, Risk Assessment, Proteinuria urine, Proteinuria diagnosis, Heart Failure urine, Heart Failure mortality, Heart Failure physiopathology, Stroke Volume, Proteomics methods, Biomarkers urine, Biomarkers blood, Angiopoietin-Like Protein 2
Abstract

Background: Although several studies have addressed plasma proteomics in heart failure with preserved ejection fraction, limited data are available on the prognostic value of urinary proteomics. The objective of our study was to identify urinary proteins/peptides associated with death and heart failure admission in patients with heart failure with preserved ejection fraction., Methods and Results: The study population included participants enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The relationship between urine protein levels and the risk of death or heart failure admission was assessed using Cox regression, in both nonadjusted analyses and adjusting for urine creatinine levels, and the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score. A total of 426 (12.4%) TOPCAT participants had urinary protein data and were included. There were 40 urinary proteins/peptides significantly associated with death or heart failure admission in nonadjusted analyses, 21 of which were also significant adjusted analyses. Top proteins in the adjusted analysis included ANGPTL2 (angiopoietin-like protein 2) (hazard ratio [HR], 0.5731 [95% CI, 0.47-0.7]; P =3.13E-05), AMY2A (α amylase 2A) (HR, 0.5496 [95% CI, 0.44-0.69]; P =0.0001), and DNASE1 (deoxyribonuclease-1) (HR, 0.5704 [95% CI, 0.46-0.71]; P =0.0002). Higher urinary levels of proteins involved in fibrosis (collagen VI α-1, collagen XV α-1), metabolism (pancreatic α-amylase 2A/B, mannosidase α class 1A member 1), and inflammation (heat shock protein family D member 1, inducible T cell costimulatory ligand) were associated with a lower risk of death or heart failure admission., Conclusions: Our study identifies several novel associations between urinary proteins/peptides and outcomes in heart failure with preserved ejection fraction. Many of these associations are independent of clinical risk scores and may aid in risk stratification in this patient population.

Published
2024
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