title: A yeast-based screen reveals that sulfasalazine inhibits tetrahydrobiopterin biosynthesis.
abstract: We introduce an approach for detection of drug-protein interactions that combines a new yeast three-hybrid screening for identification of interactions with affinity chromatography for their unambiguous validation. We applied the methodology to the profiling of clinically approved drugs, resulting in the identification of previously known and unknown drug-protein interactions. In particular, we were able to identify off-targets for erlotinib and atorvastatin, as well as an enzyme target for the anti-inflammatory drug sulfasalazine. We demonstrate that sulfasalazine and its metabolites, sulfapyridine and mesalamine, are inhibitors of the enzyme catalyzing the final step in the biosynthesis of the cofactor tetrahydrobiopterin. The interference with tetrahydrobiopterin metabolism provides an explanation for some of the beneficial and deleterious properties of sulfasalazine and furthermore suggests new and improved therapies for the drug. This work thus establishes a powerful approach for drug profiling and provides new insights in the mechanism of action of clinically approved drugs.
authors.affiliation: Institute of Chemical Sciences and Engineering, Institute of Bioengineering, National Centre of Competence in Research Chemical Biology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chidley
authors.forename: Hirohito
authors.initials: H
authors.lastname: Haruki
authors.forename: Miriam Grønlund
authors.initials: MG
authors.lastname: Pedersen
authors.forename: Evelyne
authors.initials: E
authors.lastname: Muller
authors.forename: Kai
authors.initials: K
authors.lastname: Johnsson
mesh_terms: D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors; D019804:Mesalamine; D008722:Methods; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D013427:Sulfapyridine; D012460:Sulfasalazine / Q000494:pharmacology*; D020798:Two-Hybrid System Techniques
chemical_list: D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D001708:Biopterins; D012460:Sulfasalazine; D019804:Mesalamine; C003402:sapropterin; D013427:Sulfapyridine