Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT).
Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT).
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DOI：
10.1021/acs.jmedchem.2c00791
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发表时间：
2022-09-08
影响因子：
7.3
通讯作者：
Rao, Srinivasa P. S.
中科院分区：
文献类型：
--
作者：
Koester, Dennis C.;Marx, Vanessa M.;Williams, Sarah;Jiricek, Jan;Dauphinais, Maxime;Rene, Olivier;Miller, Sarah L.;Zhang, Lei;Patra, Debjani;Chen, Yen-Liang;Cheung, Harry;Gable, Jonathan;Lakshminarayana, Suresh B.;Osborne, Colin;Galarneau, Jean-Rene;Kulkarni, Upendra;Richmond, Wendy;Bretz, Angela;Xiao, Linda;Supek, Frantisek;Wiesmann, Christian;Honnappa, Srinivas;Be, Celine;Maeser, Pascal;Kaiser, Marcel;Ritchie, Ryan;Barrett, Michael P.;Diagana, Thierry T.;Sarko, Christopher;Rao, Srinivasa P. S.
人类非洲锥虫病（HAT）是一种由锥虫属动质体寄生虫引起的媒介传播疾病。该疾病分为两个阶段，即血淋巴血阶段和脑膜脑阶段。在后一阶段，寄生虫对大脑造成不可逆的损伤，导致睡眠周期中断，如果不治疗是致命的。口服生物可利用的治疗是高度期望的。在这项研究中，我们提出了一种脑渗透性，寄生虫选择性20 S蛋白酶体抑制剂，从HTS单次击中到药物候选化合物7，该化合物7在II期小鼠疗效模型中显示出治愈，该抑制剂被快速优化。在这里，我们描述了由冷冻电子显微镜和计算机模拟模型指导的命中扩展和铅优化活动，以预测脑-血浆分配系数Kp作为优先合成化合物的重要参数。该模型结合体外和体内实验，使我们能够推进具有良好的未结合脑血浆比（Kp，uu）的化合物，以治疗CNS疾病，如HAT。
Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma 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 7 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 in silico model to predict the brain-to-plasma partition coefficient Kp 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 (Kp,uu) to cure a CNS disease such as HAT.
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影响因子：
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作者：
Lewis MD;Francisco AF;Taylor MC;Kelly JM
通讯作者：
Kelly JM
影响因子：
2.4
作者：
BARRY, JD;EMERY, DL
通讯作者：
EMERY, DL
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作者：
Kennedy, Peter G. E.
通讯作者：
Kennedy, Peter G. E.
影响因子：
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通讯作者：
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通讯作者：
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