Vito, Alessio (2024) Targeting enzymes with marine-derived small molecules in search of new multitarget inhibitors to develop new treatments for type 2 diabetes mellitus and inflammatory diseases. [Tesi di dottorato]

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Abstract

Even more than their terrestrial counterpart, marine natural products are considered privileged structures capable to bind and modulate a plethora of protein targets, positioning them as pre-validated starting points for the design of compounds libraries for new pharmaceutical leads discovery. The wide chemical space covered by the unique and often complex scaffolds of marine metabolites can be indeed explored and exploited for drug discovery through the design and production of libraries of diverse natural product-inspired compound. These tasks can take full advantage of current medicinal chemistry strategies and methodologies. In this context, the research work reported below focused on the pharmacological characterization of phospoeleganin, a phosphorylated polyketide of marine origin endowed with antidiabetic properties, performed also by using several fragments libraries inspired to the natural product and generated by organic synthesis. These focused chemical libraries have been developed combining the principles of fragment-based drug discovery and diversity-oriented synthesis. They were composed of both semi-synthetic fragments of the polyketide and small molecules representative of its most functionalized portion, aiming both at investigating the essential requirements necessary to ensure pharmacological activities and at identifying new small molecules with multitarget activity to be further optimized in search of new therapeutics for multifactorial diseases. The study confirmed the insulin-sensitizing behavior of the polyketide, clarified its effects on insulin resistance and glucose homeostasis in liver cells, as well as demonstrated it as a promising multitarget agent capable of interacting with as many as three targets involved in metabolic diseases. Moreover, it pointed out to some new candidates as antidiabetic leads with more synthetic tractability with respect to the natural complex metabolite.

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