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5buh

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Revision as of 06:08, 1 November 2017

Influenza PB2 bound to a hydroxymethyl azaindole inhibitor

Structural highlights

5buh is a 1 chain structure with sequence from I75a0. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	PB2 (I75A0)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PB2_I75A0] 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. Binds the cap of the target pre-RNA which is subsequently cleaved after 10-13 nucleotides by PA. Plays a role in the initiation of the viral genome replication and modulates the activity of the ribonucleoprotein (RNP) complex. In addition, participates in the inhibition of type I interferon induction through interaction with the host mitochondrial antiviral signaling protein MAVS.[UniProtKB:P03428]

Publication Abstract from PubMed

JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism. Incorporation of a ring nitrogen generated 7-azaindazole analogues that were equipotent to the parent 2-H-7-azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7-azaindole analogues with enhanced AO stability and we present data for one such compound (12) that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogues have the potential to be further developed as anti-influenza agents for the treatment of influenza.

Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza.,Bandarage UK, Clark MP, Perola E, Gao H, Jacobs MD, Tsai A, Gillespie J, Kennedy JM, Maltais F, Ledeboer MW, Davies I, Gu W, Byrn RA, Nti Addae K, Bennett H, Leeman JR, Jones SM, O'Brien C, Memmott C, Bennani Y, Charifson PS ACS Med Chem Lett. 2017 Jan 18;8(2):261-265. doi: 10.1021/acsmedchemlett.6b00487., eCollection 2017 Feb 9. PMID:28197323^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Bandarage UK, Clark MP, Perola E, Gao H, Jacobs MD, Tsai A, Gillespie J, Kennedy JM, Maltais F, Ledeboer MW, Davies I, Gu W, Byrn RA, Nti Addae K, Bennett H, Leeman JR, Jones SM, O'Brien C, Memmott C, Bennani Y, Charifson PS. Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza. ACS Med Chem Lett. 2017 Jan 18;8(2):261-265. doi: 10.1021/acsmedchemlett.6b00487., eCollection 2017 Feb 9. PMID:28197323 doi:http://dx.doi.org/10.1021/acsmedchemlett.6b00487

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5buh"

@@ Line 3: / Line 3: @@
 <StructureSection load='5buh' size='340' side='right' caption='[[5buh]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5buh]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BUH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BUH FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5buh]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/I75a0 I75a0]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BUH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BUH FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4V7:N-[(1R,3S)-3-({5-FLUORO-2-[5-FLUORO-2-(HYDROXYMETHYL)-1H-PYRROLO[2,3-B]PYRIDIN-3-YL]PYRIMIDIN-4-YL}AMINO)CYCLOHEXYL]PYRROLIDINE-1-CARBOXAMIDE'>4V7</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PB2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=383596 I75A0])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5buh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5buh OCA], [http://pdbe.org/5buh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5buh RCSB], [http://www.ebi.ac.uk/pdbsum/5buh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5buh ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: I75a0]]
 [[Category: Jacobs, M D]]
 [[Category: Immune system]]

5buh

From Proteopedia

Revision as of 06:08, 1 November 2017

Influenza PB2 bound to a hydroxymethyl azaindole inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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