2. Academic Validation
  3. Synthesis and biological evaluation of a library of hybrid derivatives as inhibitors of influenza virus PA-PB1 interaction

Synthesis and biological evaluation of a library of hybrid derivatives as inhibitors of influenza virus PA-PB1 interaction

  • Eur J Med Chem. 2018 Sep 5:157:743-758. doi: 10.1016/j.ejmech.2018.08.032.
Ilaria D'Agostino 1,  Ilaria Giacchello 2,  Giulio Nannetti 3,  Anna Lucia Fallacara 1,  Davide Deodato 1,  Francesca Musumeci 2,  Giancarlo Grossi 2,  Giorgio Palù 3,  Ylenia Cau 1,  Iuni Margaret Trist 1,  Arianna Loregian 4,  Silvia Schenone 5,  Maurizio Botta 6
Affiliations

Affiliations

  • 1 Dipartimento di Biotecnologie, Chimica e Farmacia, Università; Degli Studi di Siena, Via A. Moro, I-53100 Siena, Italy.
  • 2 Dipartimento di Farmacia, Università Degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
  • 3 Dipartimento di Medicina Molecolare, Università; Degli Studi di Padova, Via A. Gabelli 63, I-35121 Padova, Italy.
  • 4 Dipartimento di Medicina Molecolare, Università; Degli Studi di Padova, Via A. Gabelli 63, I-35121 Padova, Italy. Electronic address: arianna.loregian@unipd.it.
  • 5 Dipartimento di Farmacia, Università Degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy. Electronic address: schensil@unige.it.
  • 6 Dipartimento di Biotecnologie, Chimica e Farmacia, Università; Degli Studi di Siena, Via A. Moro, I-53100 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, United States; Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy.
PMID: 30142611 DOI: 10.1016/j.ejmech.2018.08.032
Abstract

The limited treatment options against Influenza Virus along with the growing public health concerns regarding the continuous emergence of drug-resistant viruses make essential the development of new anti-flu agents with novel mechanisms of action. One of the most attractive targets is the interaction between two subunits of the RNA-dependent RNA polymerase, PA and PB1. Herein we report the rational design of hybrid compounds starting from a 3-cyano-4,6-diphenylpyridine scaffold recently identified as disruptor of PA-PB1 interactions. Guided by the previously reported SAR data, a library of Amino Acid Derivatives was synthesized. The biological evaluation led to the identification of new PA-PB1 inhibitors, that do not show appreciable toxicity. Molecular modeling shed further lights on the inhibition mechanism of these compounds.

Keywords

Amino acid coupling; Anti-Influenza; Diphenyl-pyridine; PA-PB1; RdRp; SPPS.

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