Abstract

Diversity-oriented synthesis of small molecule peptidomimetics to address lead identification in drug discovery

Andrea Trabocchi, Assistant Professor, University of Florence

Modern advances in chemical biology include the improvement of screening methods, the introduction of bioinformatics methods to unravel biological pathways, and the development of high-quality chemical libraries. In this view, Diversity-Oriented Synthesis (DOS) gathered interest to explore systematically the chemical space by generating small-molecule collections as probes to investigate biological pathways. DOS consists of synthesizing structurally diverse compounds from a complexity-generating reaction followed by cyclization steps and appendage diversity. Also, chemical genetics emerged as a tool in chemical biology for its role in selecting small molecules capable to induce a biological phenotype or to interact with a gene product. Our efforts in this field are focused on the production of diversity-oriented molecules of peptidomimetic nature as tool addressing protein-protein interactions, taking advantage of amino acid- and sugar-derived polyfunctional building blocks to be applied in couple-pair synthetic approaches. We are applying such peptidomimetic scaffolds to biological evaluation using cell growth as a phenotypic screening on yeast deletant strains to identify hit compounds in the discovery of novel antifungal and anticancer agents, and to dissect their mode of action.