+検索条件
-Structure paper
タイトル | Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT). |
---|---|
ジャーナル・号・ページ | J Med Chem, Vol. 65, Issue 17, Page 11776-11787, Year 2022 |
掲載日 | 2022年9月8日 |
著者 | Dennis C Koester / Vanessa M Marx / Sarah Williams / Jan Jiricek / Maxime Dauphinais / Olivier René / Sarah L Miller / Lei Zhang / Debjani Patra / Yen-Liang Chen / Harry Cheung / Jonathan Gable / Suresh B Lakshminarayana / Colin Osborne / Jean-Rene Galarneau / Upendra Kulkarni / Wendy Richmond / Angela Bretz / Linda Xiao / Frantisek Supek / Christian Wiesmann / Srinivas Honnappa / Celine Be / Pascal Mäser / Marcel Kaiser / Ryan Ritchie / Michael P Barrett / Thierry T Diagana / Christopher Sarko / Srinivasa P S Rao / |
PubMed 要旨 | 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- ...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. |
リンク | J Med Chem / PubMed:35993839 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.7 Å |
構造データ | EMDB-15025, PDB-7zyj: |
化合物 | ChemComp-KFC: |
由来 |
|
キーワード | HYDROLASE / proteasome. Cryo-EM / Inhibitor |