Structural highlights
Function[Q6E3N3_9INFA] Plays an essential role in transcription initiation and cap-stealing mechanism, in which cellular capped pre-mRNAs are used to generate primers for viral transcription. Recognizes and binds the 7-methylguanosine-containing cap of the target pre-RNA which is subsequently cleaved after 10-13 nucleotides by the viral protein PA. Plays a role in the initiation of the viral genome replication and modulates the activity of the ribonucleoprotein (RNP) complex.[HAMAP-Rule:MF_04062][SAAS:SAAS01041023] Publication Abstract from PubMedIn the search for novel influenza inhibitors we evaluated 7-fluoro-substituted indoles as bioisosteric replacements for the 7-azaindole scaffold of Pimodivir, a PB2 (polymerase basic protein 2) inhibitor currently in clinical development. Specifically, a 5,7-difluoroindole derivative 11a was identified as a potent and metabolically stable influenza inhibitor. 11a demonstrated a favorable oral pharmacokinetic profile and in vivo efficacy in mice. In addition, it was found that 11a was not at risk of metabolism via aldehyde oxidase, an advantage over previously described inhibitors of this class. The crystal structure of 11a bound to influenza A PB2 cap region is disclosed here and deposited to the PDB. Design, Synthesis, and Biological Evaluation of Novel Indoles Targeting the Influenza PB2 Cap Binding Region.,McGowan DC, Balemans W, Embrechts W, Motte M, Keown JR, Buyck C, Corbera J, Funes M, Moreno L, Cooymans L, Tahri A, Eymard J, Stoops B, Strijbos R, Van den Berg J, Fodor E, Grimes JM, Koul A, Jonckers THM, Raboisson P, Guillemont J J Med Chem. 2019 Oct 30. doi: 10.1021/acs.jmedchem.9b01091. PMID:31647875[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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