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Pure Appl. Chem., 2011, Vol. 83, No. 3, pp. 687-698

Published online 2011-01-18

Chemical genetics approach to drug discovery by diversity-oriented synthesis (DOS) of peptidomimetics

Andrea Trabocchi1*, Duccio Cavalieri2 and Antonio Guarna1*

1 Department of Chemistry “Ugo Schiff”, University of Florence, Polo Scientifico e Tecnologico, Via della Lastruccia 13, I-50019, Sesto Fiorentino, Florence, Italy
2 Department of Pharmacology “Mario Aiazzi Mancini”, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy

Abstract: Chemical genetics, which relies on selecting small molecules for their ability to induce a biological phenotype or to interact with a particular gene product, is a new powerful tool for lead generation in drug discovery. Accordingly, diversity-oriented synthesis (DOS) of small-molecule peptidomimetics gives access to collections of new chemotypes bearing high structural diversity. Biological evaluation using cell growth as a phenotypic screening on Saccharomyces cerevisiae deletant strains is a powerful tool to identify new chemotypes as hit compounds in the discovery of new antifungal and anticancer agents, and also in the dissection of their mode of action. Our contribution in this field focused on the screening of morpholine-based peptidomimetic collections toward yeast deletant strains, which provided the identification of new chemotypes involved in mitochondria metabolism and respiration.