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==HIV-1 Integrase catalytic core domain complexed with allosteric inhibitor STP03-0404== | ==HIV-1 Integrase catalytic core domain complexed with allosteric inhibitor STP03-0404== | ||
<StructureSection load='7ke0' size='340' side='right'caption='[[7ke0]]' scene=''> | <StructureSection load='7ke0' size='340' side='right'caption='[[7ke0]], [[Resolution|resolution]] 2.19Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KE0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KE0 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7ke0]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KE0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KE0 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ke0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ke0 OCA], [https://pdbe.org/7ke0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ke0 RCSB], [https://www.ebi.ac.uk/pdbsum/7ke0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ke0 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=WBV:(2S)-tert-butoxy{4-(4-chlorophenyl)-2,3,6-trimethyl-1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}acetic+acid'>WBV</scene></td></tr> | ||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CAF:S-DIMETHYLARSINOYL-CYSTEINE'>CAF</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/RNA-directed_DNA_polymerase RNA-directed DNA polymerase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.49 2.7.7.49] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ke0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ke0 OCA], [https://pdbe.org/7ke0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ke0 RCSB], [https://www.ebi.ac.uk/pdbsum/7ke0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ke0 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Allosteric integrase inhibitors (ALLINIs) are a class of experimental anti-HIV agents that target the noncatalytic sites of the viral integrase (IN) and interfere with the IN-viral RNA interaction during viral maturation. Here, we report a highly potent and safe pyrrolopyridine-based ALLINI, STP0404, displaying picomolar IC50 in human PBMCs with a >24,000 therapeutic index against HIV-1. X-ray structural and biochemical analyses revealed that STP0404 binds to the host LEDGF/p75 protein binding pocket of the IN dimer, which induces aberrant IN oligomerization and blocks the IN-RNA interaction. Consequently, STP0404 inhibits proper localization of HIV-1 RNA genomes in viral particles during viral maturation. Y99H and A128T mutations at the LEDGF/p75 binding pocket render resistance to STP0404. Extensive in vivo pharmacological and toxicity investigations demonstrate that STP0404 harbors outstanding therapeutic and safety properties. Overall, STP0404 is a potent and first-in-class ALLINI that targets LEDGF/p75 binding site and has advanced to a human trial. | |||
A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site.,Maehigashi T, Ahn S, Kim UI, Lindenberger J, Oo A, Koneru PC, Mahboubi B, Engelman AN, Kvaratskhelia M, Kim K, Kim B PLoS Pathog. 2021 Jul 22;17(7):e1009671. doi: 10.1371/journal.ppat.1009671., eCollection 2021 Jul. PMID:34293041<ref>PMID:34293041</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7ke0" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Kvaratskhelia M]] | [[Category: RNA-directed DNA polymerase]] | ||
[[Category: Lindenberger | [[Category: Kvaratskhelia, M]] | ||
[[Category: Lindenberger, J J]] | |||
[[Category: Hiv]] | |||
[[Category: Inhibitor]] | |||
[[Category: Integrase]] | |||
[[Category: Transferase-inhibitor complex]] | |||
Revision as of 13:32, 6 April 2022
HIV-1 Integrase catalytic core domain complexed with allosteric inhibitor STP03-0404HIV-1 Integrase catalytic core domain complexed with allosteric inhibitor STP03-0404
Structural highlights
Publication Abstract from PubMedAllosteric integrase inhibitors (ALLINIs) are a class of experimental anti-HIV agents that target the noncatalytic sites of the viral integrase (IN) and interfere with the IN-viral RNA interaction during viral maturation. Here, we report a highly potent and safe pyrrolopyridine-based ALLINI, STP0404, displaying picomolar IC50 in human PBMCs with a >24,000 therapeutic index against HIV-1. X-ray structural and biochemical analyses revealed that STP0404 binds to the host LEDGF/p75 protein binding pocket of the IN dimer, which induces aberrant IN oligomerization and blocks the IN-RNA interaction. Consequently, STP0404 inhibits proper localization of HIV-1 RNA genomes in viral particles during viral maturation. Y99H and A128T mutations at the LEDGF/p75 binding pocket render resistance to STP0404. Extensive in vivo pharmacological and toxicity investigations demonstrate that STP0404 harbors outstanding therapeutic and safety properties. Overall, STP0404 is a potent and first-in-class ALLINI that targets LEDGF/p75 binding site and has advanced to a human trial. A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site.,Maehigashi T, Ahn S, Kim UI, Lindenberger J, Oo A, Koneru PC, Mahboubi B, Engelman AN, Kvaratskhelia M, Kim K, Kim B PLoS Pathog. 2021 Jul 22;17(7):e1009671. doi: 10.1371/journal.ppat.1009671., eCollection 2021 Jul. PMID:34293041[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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