4,6-diphenylpyridines as promising novel anti-influenza agents targeting the PA-PB1 protein-protein interaction: structure-activity relationships.

I.M. Trist, G. Nannetti, C. Tintori, A.L. Fallacara, D. Deodato, B. Mercorrelli, G. Palu, M. Wijtmans, T. Gospodova, E.S. Edink, M.H.P. Verheij, I.J.P. de Esch, L. Viteva, A. Loregian, M. Botta

Research output: Contribution to JournalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)2688-2703
JournalJournal of Medicinal Chemistry
Volume59
Issue number6
DOIs
Publication statusPublished - 2016

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Structure-Activity Relationship
Human Influenza
Antiviral Agents
Proteins
Pyridines
Influenza Vaccines
Viral RNA
DNA-Directed RNA Polymerases
Communicable Diseases
Public Health
Morbidity
Mortality
Therapeutics

Cite this

Trist, I.M. ; Nannetti, G. ; Tintori, C. ; Fallacara, A.L. ; Deodato, D. ; Mercorrelli, B. ; Palu, G. ; Wijtmans, M. ; Gospodova, T. ; Edink, E.S. ; Verheij, M.H.P. ; de Esch, I.J.P. ; Viteva, L. ; Loregian, A. ; Botta, M. / 4,6-diphenylpyridines as promising novel anti-influenza agents targeting the PA-PB1 protein-protein interaction: structure-activity relationships. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 6. pp. 2688-2703.
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title = "4,6-diphenylpyridines as promising novel anti-influenza agents targeting the PA-PB1 protein-protein interaction: structure-activity relationships.",
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.",
author = "I.M. Trist and G. Nannetti and C. Tintori and A.L. Fallacara and D. Deodato and B. Mercorrelli and G. Palu and M. Wijtmans and T. Gospodova and E.S. Edink and M.H.P. Verheij and {de Esch}, I.J.P. and L. Viteva and A. Loregian and M. Botta",
year = "2016",
doi = "10.1021/acs.jmedchem.5b01935",
language = "English",
volume = "59",
pages = "2688--2703",
journal = "Journal of Medicinal Chemistry",
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Trist, IM, Nannetti, G, Tintori, C, Fallacara, AL, Deodato, D, Mercorrelli, B, Palu, G, Wijtmans, M, Gospodova, T, Edink, ES, Verheij, MHP, de Esch, IJP, Viteva, L, Loregian, A & Botta, M 2016, '4,6-diphenylpyridines as promising novel anti-influenza agents targeting the PA-PB1 protein-protein interaction: structure-activity relationships.' Journal of Medicinal Chemistry, vol. 59, no. 6, pp. 2688-2703. https://doi.org/10.1021/acs.jmedchem.5b01935

4,6-diphenylpyridines as promising novel anti-influenza agents targeting the PA-PB1 protein-protein interaction: structure-activity relationships. / Trist, I.M.; Nannetti, G.; Tintori, C.; Fallacara, A.L.; Deodato, D.; Mercorrelli, B.; Palu, G.; Wijtmans, M.; Gospodova, T.; Edink, E.S.; Verheij, M.H.P.; de Esch, I.J.P.; Viteva, L.; Loregian, A.; Botta, M.

In: Journal of Medicinal Chemistry, Vol. 59, No. 6, 2016, p. 2688-2703.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - 4,6-diphenylpyridines as promising novel anti-influenza agents targeting the PA-PB1 protein-protein interaction: structure-activity relationships.

AU - Trist, I.M.

AU - Nannetti, G.

AU - Tintori, C.

AU - Fallacara, A.L.

AU - Deodato, D.

AU - Mercorrelli, B.

AU - Palu, G.

AU - Wijtmans, M.

AU - Gospodova, T.

AU - Edink, E.S.

AU - Verheij, M.H.P.

AU - de Esch, I.J.P.

AU - Viteva, L.

AU - Loregian, A.

AU - Botta, M.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.5b01935

DO - 10.1021/acs.jmedchem.5b01935

M3 - Article

VL - 59

SP - 2688

EP - 2703

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 6

ER -