4,6-diphenylpyridines as promising novel anti-influenza agents targeting the PA–PB1 protein–protein interaction: structure–activity relationships exploration with the aid of molecular modeling

Trist, Iuni M. L., Nannetti, Giulio ORCID: https://orcid.org/0000-0003-3227-1537, Tintori, Cristina, Fallacara, Anna Lucia, Deodato, Davide, Mercorelli, Beatrice, Palù, Giorgio, Wijtmans, Maikel, Gospodova, Tzveta, Edink, Ewald, Verheij, Mark, de Esch, Iwan, Viteva, Lilia, Loregian, Arianna and Botta, Maurizio 2016. 4,6-diphenylpyridines as promising novel anti-influenza agents targeting the PA–PB1 protein–protein interaction: structure–activity relationships exploration with the aid of molecular modeling. Journal of Medicinal Chemistry 59 (6) , pp. 2688-2703. 10.1021/acs.jmedchem.5b01935

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Abstract

Influenza is an infectious disease that represents an important public health burden, with high impact on the global morbidity, mortality, and economy. The poor protection and the need of annual updating of the anti-influenza vaccine, added to the rapid emergence of viral strains resistant to current therapy make the need for antiviral drugs with novel mechanisms of action compelling. In this regard, the viral RNA polymerase is an attractive target that allows the design of selective compounds with reduced risk of resistance. In previous studies we showed that the inhibition of the polymerase acidic protein-basic protein 1 (PA–PB1) interaction is a promising strategy for the development of anti-influenza agents. Starting from the previously identified 3-cyano-4,6-diphenyl-pyridines, we chemically modified this scaffold and explored its structure–activity relationships. Noncytotoxic compounds with both the ability of disrupting the PA–PB1 interaction and antiviral activity were identified, and their mechanism of target binding was clarified with molecular modeling simulations.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	24 September 2018
Date of Acceptance:	15 December 2015
Last Modified:	25 Nov 2024 02:15
URI:	https://orca.cardiff.ac.uk/id/eprint/115207

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