5UJ2

Crystal structure of HCV NS5B genotype 2A JFH-1 isolate with S15G E86Q E87Q C223H V321I mutations and Delta8 neta hairpoin loop deletion in complex with GS-639476 (diphsohate version of GS-9813), Mn2+ and symmetrical primer template 5'-AUAAAUUU

Summary for 5UJ2

• Entry DOI: 10.2210/pdb5uj2/pdb
• Related: 4WTD 4WTG
• Descriptor: RNA (5'-R(*AP*UP*AP*AP*AP*UP*UP*U)-3'), Genome polyprotein, MANGANESE (II) ION, ... (6 entities in total)
• Functional Keywords: hcv, viral, ns5b, rdrp, resistance mutation, sofosbuvir, sovaldi, virunon, gs7977-dp, gs-639476, template, primer, immune system-rna complex, immune system/rna
• Biological source: Escherichia coli; More
• Cellular location: Virion : R9TEU1
• Total number of polymer chains: 3
• Total formula weight: 69497.88

Authors

Edwards, T.E.,Fox III, D.,Appleby, T.C.,Murakami, E.,Rey, A.,McGrath, M.E. (deposition date: 2017-01-16, release date: 2017-03-22, Last modification date: 2023-10-04)

Primary citation

Kirschberg, T.A.,Metobo, S.,Clarke, M.O.,Aktoudianakis, V.,Babusis, D.,Barauskas, O.,Birkus, G.,Butler, T.,Byun, D.,Chin, G.,Doerffler, E.,Edwards, T.E.,Fenaux, M.,Lee, R.,Lew, W.,Mish, M.R.,Murakami, E.,Park, Y.,Squires, N.H.,Tirunagari, N.,Wang, T.,Whitcomb, M.,Xu, J.,Yang, H.,Ye, H.,Zhang, L.,Appleby, T.C.,Feng, J.Y.,Ray, A.S.,Cho, A.,Kim, C.U.
Discovery of a 2'-fluoro-2'-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties.
Bioorg. Med. Chem. Lett., 27:1840-1847, 2017

PubMed Abstract: A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.

PubMed: 28274633
DOI: 10.1016/j.bmcl.2017.02.037

Experimental method

X-RAY DIFFRACTION (2.9 Å)