6qm7

Leishmania tarentolae proteasome 20S subunit complexed with GSK3494245

spinqualitylabelsall models 6qm7, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6qm7 is a 28 chain structure with sequence from Leishmania tarentolae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: J6E Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the beta5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the beta4 and beta5 proteasome subunits. This induced pocket exploits beta4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials. Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition.,Wyllie S, Brand S, Thomas M, De Rycker M, Chung CW, Pena I, Bingham RP, Bueren-Calabuig JA, Cantizani J, Cebrian D, Craggs PD, Ferguson L, Goswami P, Hobrath J, Howe J, Jeacock L, Ko EJ, Korczynska J, MacLean L, Manthri S, Martinez MS, Mata-Cantero L, Moniz S, Nuhs A, Osuna-Cabello M, Pinto E, Riley J, Robinson S, Rowland P, Simeons FRC, Shishikura Y, Spinks D, Stojanovski L, Thomas J, Thompson S, Viayna Gaza E, Wall RJ, Zuccotto F, Horn D, Ferguson MAJ, Fairlamb AH, Fiandor JM, Martin J, Gray DW, Miles TJ, Gilbert IH, Read KD, Marco M, Wyatt PG Proc Natl Acad Sci U S A. 2019 Apr 8. pii: 1820175116. doi:, 10.1073/pnas.1820175116. PMID:30962368 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Proteasome 3D structures

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