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ANR funded project

Innovation biomédicale (DS0404) 2014
Projet FungiBET

Investigating a potential new anti-fungal drug target: Structure, function and inhibition of fungal BET bromodomains

Overview: The central hypothesis of this project is that inhibition of the fungal BET family protein Bdf1 is a valid therapeutic strategy to combat invasive fungal infections. The project aims to verify this hypothesis for Candida albicans and Candida glabrata, the two most common pathogenic yeasts of humans.

Biomedical Relevance: Invasive fungal infections are a major cause of morbidity and mortality, with over 800,000 deaths per year worldwide. Candida species are the most common nosocomial pathogens. Of these, C. albicans and C. glabrata rank first and second in isolation frequency and cause approximately 70% of all candidemia. Currently, only four drug classes are available to treat candidemia and other systemic fungal infections. These drugs act by targeting the fungal cell wall (echinocandins) or cell membrane (polyenes, azoles) or by inhibiting nucleic acid synthesis (flucytosine). The limited number of anti-fungal strategies, the high cost and toxicity of available drugs and a rise in drug-resistant strains poses an urgent need for the development of novel therapeutic agents.

Rationale: We propose to investigate a potentially new antifungal strategy, inspired by recently discovered anti-cancer compounds that target a specific family of transcriptional regulators – the BET (“Bromodomain and Extra-Terminal”) proteins. BET proteins bind chromatin through their two bromodomains (BD1 and BD2), small helical domains which specifically recognize histones acetylated on lysine residues. Several recently discovered BET bromodomain inhibitors have been used to validate human BET bromodomain inhibition as a therapeutic strategy for numerous cancers and other pathologies. Genetic evidence in S. cerevisiae and C. albicans implicates the fungal BET protein, Bdf1, as a potentially new antifungal drug target.

Preliminary data: We have determined the crystal structures of Bdf1 bromodomains BD1 and BD2 from S. cerevisiae and from C. albicans. The ligand binding pockets of these structures are distinct from those of human BET proteins, raising the prospect of identifying a small molecule inhibitor selective for the fungal bromodomains. We developed AlphaScreen and FRET-based assays which will allow the high-throughput screening of chemical libraries to identify Bdf1 bromodomain inhibitors. In parallel, we established an in silico protocol to perform virtual screening on our Bdf1 crystal structures, and in a preliminary screen identified a candidate inhibitor of C. albicans Bdf1 BD2.

Objectives: The goal of this project is to establish proof-of-concept that chemical inhibition of fungal Bdf1 bromodomains is a valid anti-fungal therapeutic strategy. The specific aims are to: (i) investigate the structure and function of Bdf1 in C. albicans and C. glabrata; (ii) verify Bdf1 bromodomain inhibition as a valid antifungal therapeutic strategy; (iii) to develop chemical compounds that selectively inhibit Bdf1 bromodomains and demonstrate their translational potential into a novel class of antifungal drug.

Consortium: This project is a collaboration of research teams in Grenoble (led by Carlo Petosa, Jerome Govin and Muriel Cornet) and Los Angeles (led by Charles McKenna). The work envisaged is a comprehensive effort that combines expertise in structural biology (Petosa), yeast genetics and epigenetics (Govin), medical mycology (Cornet), and synthetic organic and medicinal chemistry (McKenna).

Expected results: This project should advance our understanding of Bdf1 function, yield selective small-molecule inhibitors of Bdf1 bromodomains and verify whether Bdf1 bromodomain inhibition is a valid antifungal therapy. A successful outcome is expected to generate patentable intellectual property and technology transfer opportunites for industry, paving the way for subsequent lead optimization and for a phase I clinical trial.

Partners

Inserm U1038 Inserm U1038

IBS Institut de Biologie Structurale

TIMC-IMAG Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble

USC University of Southern California, Los Angeles

ANR grant: 370 577 euros
Beginning and duration: décembre 2014 - 36 mois

 

ANR Programme: Innovation biomédicale (DS0404) 2014

Project ID: ANR-14-CE16-0027

Project coordinator:
Monsieur Carlo Petosa (Institut de Biologie Structurale)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.