The continual emergence of resistant and non-susceptible strains provides a compelling reason to continue the search for entirely new classes of antifungal drugs Anacor Pharmaceuticals, Inc has discovered novel compounds with antifungal activity (in some cases with MIC for Candida spp. < 1ug/ml. Members of this class have been shown to have favorable pharmacokinetics and safety in mice. Their molecular target in fungi is unknown. Here, we outline a short, focused and highly integrated three-pan proposal aimed at discovering the molecular target of these novel compounds. The process will simultaneously move forward the lead optimization program so that at the end of these studies, the project will be poised to enter preclinical development activities. To accomplish our goal of identifying the target of these novel compounds, we propose to combine the expertise and resources of three highly qualified principal investigators: Dr. Jacob Planner, Anacor Pharmaceuticals (Project One: Synthetic and Medicinal Chemistry) Dr. Carolyn BellJnger-Kawahara, Anacor Pharmaceuticals (Project Two: Mode of Action Studies) Dr. Ron Davis, Stanford Genome Technology Center (Project Three: Chemical Genornics) Aim 1.1 Creation of tool compounds for use in target identification studies.
Aim 1. 2 Lead expansion.
Aim 1. 3 Optimization of potency.
Aim 2. 1 Potency, Spectrum, Cytotoxicity Aim 2.2 Macromolecular Synthesis Studies Airn 2.3 De Novo Resistance Aim 2.4 Target Identification through Affinity Methods Aim 2.5 Assay Development Aim 3.1 Prescreening of compounds Aim 3.2 Whole genome screen and validation (Saccharomyces cerevisias) Aim 3.3 Candida Expression Array Aim 3.4 Data access and dissemination
| Seiradake, Elena; Mao, Weimin; Hernandez, Vincent et al. (2009) Crystal structures of the human and fungal cytosolic Leucyl-tRNA synthetase editing domains: A structural basis for the rational design of antifungal benzoxaboroles. J Mol Biol 390:196-207 |
| Rock, Fernando L; Mao, Weimin; Yaremchuk, Anya et al. (2007) An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science 316:1759-61 |
