A systems biology approach to dissection of the effects of small bicyclic peptidomimetics on a panel of saccharomyces cerevisiae mutants.
In recent years, an approach called "chemical genetics" has been adopted in drug research to discover and validate new targets and to identify and optimize leads by high throughput screening. In this work, we tested the ability of a library of small peptidomimetics to induce phenotypic effects with functional implications on a panel of strains of the budding yeast Saccharomyces cerevisiae, both wild type and mutants, for respiratory function and multidrug resistance. Further elucidation of the function of these peptidomimetics was assessed by testing the effects of the compound with the most prominent inhibitory activity, 089, on gene expression using DNA microarrays. Pathway analysis showed the involvement of such a molecule in inducing oxidative damage through alterations in mitochondrial functions. Transcriptional experiments were confirmed by increased levels of ROS and activation of mitochondrial membrane potential. Our results demonstrate the influence of a functional HAP1 gene in the performance of S. cerevisiae as a model system.
Stefanini
Irene
I
Department of Pharmacology "Mario Aiazzi Mancini", University of Florence, 50139 Florence, Italy.
Trabocchi
Andrea
A
Marchi
Emmanuela
E
Guarna
Antonio
A
Cavalieri
Duccio
D
D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D008826:Microbial Sensitivity Tests; D008928:Mitochondria / Q000187:drug effects; D009154:Mutation; D010456:Peptides, Cyclic / Q000737:chemistry*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects* / Q000235:genetics*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D049490:Systems Biology / Q000379:methods*; D014158:Transcription, Genetic / Q000187:drug effects
D010456:Peptides, Cyclic; D054852:Small Molecule Libraries