View source for 8olu


==Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide==
<StructureSection load='8olu' size='340' side='right'caption='[[8olu]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8olu]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_tarentolae Leishmania tarentolae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8OLU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OLU FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.59&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VYW:~{N}-[3-(cyclopropylcarbamoyl)phenyl]-6-oxidanylidene-1-(phenylmethyl)pyridazine-3-carboxamide'>VYW</scene></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=8olu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8olu OCA], [https://pdbe.org/8olu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8olu RCSB], [https://www.ebi.ac.uk/pdbsum/8olu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8olu ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A0A640KZP5_LEITA A0A640KZP5_LEITA] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH.[RuleBase:RU000551]
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== Publication Abstract from PubMed ==
There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmania proteasome. A related analogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the T. cruzi proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.

Structure-Guided Design and Synthesis of a Pyridazinone Series of Trypanosoma cruzi Proteasome Inhibitors.,Thomas MG, McGonagle K, Rowland P, Robinson DA, Dodd PG, Camino-Diaz I, Campbell L, Cantizani J, Castaneda P, Conn D, Craggs PD, Edwards D, Ferguson L, Fosberry A, Frame L, Goswami P, Hu X, Korczynska J, MacLean L, Martin J, Mutter N, Osuna-Cabello M, Paterson C, Pena I, Pinto EG, Pont C, Riley J, Shishikura Y, Simeons FRC, Stojanovski L, Thomas J, Wrobel K, Young RJ, Zmuda F, Zuccotto F, Read KD, Gilbert IH, Marco M, Miles TJ, Manzano P, De Rycker M J Med Chem. 2023 Jul 28. doi: 10.1021/acs.jmedchem.3c00582. PMID:37506194<ref>PMID:37506194</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Leishmania tarentolae]]
[[Category: Rowland P]]