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Novel influenza inhibitors designed to target PB1 interactions with host importin RanBP5

G. Mohl, N. Liddle, J. Nygaard, A. Dorius, N. Lyons, J. Hodek, J. Weber, DJ. Michaelis, DD. Busath,

. 2019 ; 164 (-) : 81-90. [pub] 20190208

Jazyk angličtina Země Nizozemsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc20022790

In search of novel targets for influenza inhibitors, a site on PB1 was selected for its high conservation and probable interaction with a host protein, RanBP5, that is key to nuclear import of PB1, where it complexes with PB2, PA, and NP to transcribe viral RNA. Docking with libraries of drug-like compounds led to a selection of five candidates that bound tightly and with a pose likely to inhibit protein binding. These were purchased and tested in vitro, found to be active, and then one was synthetically expanded to explore the structure-activity relationship. The top candidates had a carboxylic acid converted to an ester and electron-withdrawing substituents added to a phenyl group in the original structure. Resistance was slow to develop, but cytotoxicity was moderately high. Nuclear localization of PB1 and in vitro polymerase activity were both strongly inhibited.

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$a Liddle, Nathan $u Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
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$a Nygaard, Joseph $u Department of Chemistry and Biochemistry, Brigham Young University, USA.
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$a Dorius, Alexander $u Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
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$a Lyons, Nathan $u Department of Chemistry and Biochemistry, Brigham Young University, USA.
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$a Hodek, Jan $u Institute of Organic Chemistry and Biochemistry of the CAS, Prague, Czech Republic.
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$a Weber, Jan $u Institute of Organic Chemistry and Biochemistry of the CAS, Prague, Czech Republic.
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$a Michaelis, David J $u Department of Chemistry and Biochemistry, Brigham Young University, USA. Electronic address: dmichaelis@byu.edu.
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$a Busath, David D $u Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA. Electronic address: david_busath@byu.edu.
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