Defining drug targets in yeast haploinsufficiency screens: application to human translational pharmacology.
A major challenge in drug discovery is to identify the cellular targets responsible for the pharmacological activity of drug candidates. In the yeast Saccharomyces cerevisiae, a heterozygous diploid mutant collection of approximately 6000 strains, in each of which one copy of a single gene is deleted, is commercially available. With this collection, it is possible to evaluate the role of each gene product in the response of cells to a drug. Drug-induced haploinsufficiency refers to the situation where a heterozygous diploid mutant is more sensitive to a drug than is the wild-type strain. Drug-induced haploinsufficiency screening has the potential to reveal pharmacological targets of drugs and those that contribute to undesired side effects, as well as gene products involved in drug transport, metabolism, or resistance. Using published studies, I present advantages and limitations of this technique and discuss its value for predicting drug targets in human cells.
Roberge
Michel
M
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. michelr@interchange.ubc.ca
D000935:Antifungal Agents / Q000494:pharmacology; D002175:Candida / Q000235:genetics; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005800:Genes, Fungal / Q000187:drug effects; D016678:Genome; D016681:Genome, Fungal; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000502:physiology*
D000935:Antifungal Agents