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
  • 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: [email protected].
  • 5. Dipartimento di Farmacia, Università Degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy. Electronic address: [email protected].
  • 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.