Publications by authors named "Paolo Vincetti"

Polyketide natural products often contain common repeat motifs, for example, propionate, acetate and deoxypropionate, and so can be synthesized by iterative processes. We report here a highly efficient iterative strategy for the synthesis of polyacetates based on boronic ester homologation that does not require functional group manipulation between iterations. This process involves sequential asymmetric diboration of a terminal alkene, forming a 1,2-bis(boronic ester), followed by regio- and stereoselective homologation of the primary boronic ester with a butenyl metallated carbenoid to generate a 1,3-bis(boronic ester).

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Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers.

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We have recently discovered a family of 2,6-diaminopurine derivatives acting as DENV inhibitors by targeting an allosteric pocket on the thumb of the viral NS5 polymerase. Although the following target-based optimization allowed conversion of the hits into broad-spectrum DENV/ZIKV inhibitors, no improvement of the antiviral potency was reached. Herein, we applied a phenotypic scaffold-morphing approach to explore additional biologically relevant chemical space around the original hits by converting the flat purine derivatives into more complex chemotypes characterized by a higher degree of saturation.

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Social and demographic changes across the world over the past 50 years have resulted in significant outbreaks of arboviruses such as dengue virus (DENV) and Zika virus (ZIKV). Despite the increased threat of infection, no approved drugs or fully protective vaccines are available to counteract the spread of DENV and ZIKV. The development of "broad-spectrum" antivirals (BSAs) that target common components of multiple viruses can be a more effective strategy to limit the rapid emergence of viral pathogens than the classic "one-bug/one-drug" approach.

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Together with estrogen receptors ERα and ERβ, the G protein-coupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens and is currently regarded as a promising target for ER-negative (ER-) and triple-negative (TN) breast cancer. Only a few selective GPER modulators have been reported to date, and their use in cancer cell lines has often led to contradictory results. Herein we report the application of virtual screening and cell-based studies for the identification of new chemical scaffolds with a specific antiproliferative effect against GPER-expressing breast cancer cell lines.

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This study describes the discovery of novel dengue virus inhibitors targeting both a crucial viral protein-protein interaction and an essential host cell factor as a strategy to reduce the emergence of drug resistance. Starting from known c-Src inhibitors, a virtual screening was performed to identify molecules able to interact with a recently discovered allosteric pocket on the dengue virus NS5 polymerase. The selection of cheap-to-produce scaffolds and the exploration of the biologically relevant chemical space around them suggested promising candidates for chemical synthesis.

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