Pharmaceuticals (Mar 2022)

Identifying Human PTP1B Enzyme Inhibitors from Marine Natural Products: Perspectives for Developing of Novel Insulin-Mimetic Drugs

  • Marcello Casertano,
  • Massimo Genovese,
  • Lucia Piazza,
  • Francesco Balestri,
  • Antonella Del Corso,
  • Alessio Vito,
  • Paolo Paoli,
  • Alice Santi,
  • Concetta Imperatore,
  • Marialuisa Menna

DOI
https://doi.org/10.3390/ph15030325
Journal volume & issue
Vol. 15, no. 3
p. 325

Abstract

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Diabetes mellitus (DM) represents a complex and multifactorial disease that causes metabolic disorders with acute and long-term serious complications. The onset of DM, with over 90% of cases of diabetes classified as type 2, implies several metabolic dysfunctions leading to consider DM a worldwide health problem. In this frame, protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) are two emerging targets involved in the development of type 2 diabetes mellitus (T2DM) and its chronic complications. Herein, we employed a marine-derived dual type inhibitor of these enzymes, phosphoeleganin, as chemical starting point to perform a fragment-based process in search for new inhibitors. Phosphoeleganin was both disassembled by its oxidative cleavage and used as model structure for the synthesis of a small library of functionalized derivatives as rationally designed analogues. Pharmacological screening supported by in silico docking analysis outlined the mechanism of action against PTP1B exerted by a phosphorylated fragment and a synthetic simplified analogue, which represent the most potent inhibitors in the library.

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