7ZYJ
Leishmania tarentolae proteasome 20S subunit in complex with compound 2
Summary for 7ZYJ
| Entry DOI | 10.2210/pdb7zyj/pdb |
| Related | 6TCZ |
| EMDB information | 15025 |
| Descriptor | Proteasome subunit alpha type, Proteasome subunit beta, Proteasome beta 6 subunit, putative, ... (15 entities in total) |
| Functional Keywords | proteasome. cryo-em, inhibitor, hydrolase |
| Biological source | Leishmania tarentolae More |
| Total number of polymer chains | 28 |
| Total formula weight | 807783.63 |
| Authors | Srinivas, H. (deposition date: 2022-05-24, release date: 2022-09-28, Last modification date: 2024-07-24) |
| Primary citation | Koester, D.C.,Marx, V.M.,Williams, S.,Jiricek, J.,Dauphinais, M.,Rene, O.,Miller, S.L.,Zhang, L.,Patra, D.,Chen, Y.L.,Cheung, H.,Gable, J.,Lakshminarayana, S.B.,Osborne, C.,Galarneau, J.R.,Kulkarni, U.,Richmond, W.,Bretz, A.,Xiao, L.,Supek, F.,Wiesmann, C.,Honnappa, S.,Be, C.,Maser, P.,Kaiser, M.,Ritchie, R.,Barrett, M.P.,Diagana, T.T.,Sarko, C.,Rao, S.P.S. Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT). J.Med.Chem., 65:11776-11787, 2022 Cited by PubMed Abstract: Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an model to predict the brain-to-plasma partition coefficient as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios () to cure a CNS disease such as HAT. PubMed: 35993839DOI: 10.1021/acs.jmedchem.2c00791 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.7 Å) |
Structure validation
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