Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 157, Issue -, Pages 743-758Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.08.032
Keywords
Anti-Influenza; PA-PB1; RdRp; Amino acid coupling; SPPS; Diphenyl-pyridine
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Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG18855]
- University of Padua (Progetto di Ricerca di Ateneo 2014) [PDA141311]
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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. (C) 2018 Elsevier Masson SAS. All rights reserved.
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