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Discovery of arginine-containing tripeptides as a new class of pancreatic lipase inhibitors

    Azzurra Stefanucci

    Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, 66100 Italy

    Authors contributed equally

    Search for more papers by this author

    ,
    Grazia Luisi

    Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, 66100 Italy

    Authors contributed equally

    Search for more papers by this author

    ,
    Gokhan Zengin

    Department of Biology, Science Faculty, Selcuk University, Konya, 42130 Turkey

    ,
    Giorgia Macedonio

    Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, 66100 Italy

    ,
    Marilisa Pia Dimmito

    Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, 66100 Italy

    ,
    Ettore Novellino

    Department of Pharmacy, ‘Federico II’ University of Naples, Naples, 80131 Italy

    &
    Adriano Mollica

    *Author for correspondence:

    E-mail Address: a.mollica@unich.it

    Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, 66100 Italy

    Published Online:https://doi.org/10.4155/fmc-2018-0216

    Aim: The inhibition of pancreatic lipase (PL) represents one of the most promising strategies in the search for novel antiobesity drugs. We propose here a pioneering course by exploring tripeptide scaffolds in the way to selective PL inhibitors. Methodology/Results: The peptide series exhibited good PL inhibitory properties in vitro, with all the strongest inhibitors sharing a central arginine, shown in silico to be relevant for the active site-directed activity. The compounds were found devoid of inhibitory properties on acetylcholinesterase. Conclusion: Present results disclosed that basic tripeptides are able to interact efficiently with the PL-binding pocket, where they adopt a binding pose suitable for functional-to-inhibition interactions with key amino acids. Main inhibitor MALA4 may be selected as lead for further optimization.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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