Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action.
Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action.
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Zelavespib揭示了伴侣调制的机制：对目标占用和延长停留时间的生化见解。
DOI：
10.3390/biomedicines11102599
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发表时间：
2023-09-22
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
在靶点停留时间长的药物通常在疾病治疗中更有效。然而，对于非共价试剂，在作用部位长时间保留的机制通常难以理解。在这种情况下，我们专注于epichaperome药物，如zelaperpib和icapambib，尽管血浆清除迅速，在非病变组织中的保留最少，代谢迅速，但仍能保持靶向结合数天。它们通过分解epichaperomes在癌症和神经退行性疾病中显示出显著的治疗价值，epichaperomes是紧密结合的伴侣蛋白和其他因子的组装体，其作为支架平台在病理上重新连接蛋白质-蛋白质相互作用。为了研究它们在体内对epichaperomes的影响，我们对zelvipib进行了药代动力学和靶向占有率测量，并在小鼠模型中生化地监测epichaperomes组装。我们的研究结果提供了证据的复杂的机制，通过zelopipib调节epichaperomes在体内。最初，当epichaperomes结合时，zeloppib被捕获，这是一种导致epichaperomes解体的机制，而epichaperomes组分的表达水平没有变化。我们认为epichaperomes的初始捕获阶段是该药物在临床环境中观察到的靶向停留时间延长的主要因素。Zelopropib在肿瘤中的停留时间似乎是由靶标分解动力学决定的，而不是由坦率的药物-靶标解结合动力学决定的。因此，zelapropib从epichaperomes的解离速率比从记录的肿瘤药代动力学特征或使用稀释系统体外测定的预期速率慢得多。这项研究揭示了使epichaperome药物有效治疗某些疾病的潜在过程。
Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. They have shown significant therapeutic value in cancer and neurodegenerative diseases by disassembling epichaperomes, which are assemblies of tightly bound chaperones and other factors that serve as scaffolding platforms to pathologically rewire protein–protein interactions. To investigate their impact on epichaperomes in vivo, we conducted pharmacokinetic and target occupancy measurements for zelavespib and monitored epichaperome assemblies biochemically in a mouse model. Our findings provide evidence of the intricate mechanism through which zelavespib modulates epichaperomes in vivo. Initially, zelavespib becomes trapped when epichaperomes bound, a mechanism that results in epichaperome disassembly, with no change in the expression level of epichaperome constituents. We propose that the initial trapping stage of epichaperomes is a main contributing factor to the extended on-target residence time observed for this agent in clinical settings. Zelavespib’s residence time in tumors seems to be dictated by target disassembly kinetics rather than by frank drug–target unbinding kinetics. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases.
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影响因子：
15
作者：
Georgi, Victoria;Schiele, Felix;Fernandez-Montalvan, Amaury
通讯作者：
Fernandez-Montalvan, Amaury
影响因子：
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作者：
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通讯作者：
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影响因子：
120.1
作者：
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影响因子：
16.6
作者：
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通讯作者：
Mollapour, Mehdi
影响因子：
16.6
作者：
Bolaender A;Zatorska D;He H;Joshi S;Sharma S;Digwal CS;Patel HJ;Sun W;Imber BS;Ochiana SO;Patel MR;Shrestha L;Shah SK;Wang S;Karimov R;Tao H;Patel PD;Martin AR;Yan P;Panchal P;Almodovar J;Corben A;Rimner A;Ginsberg SD;Lyashchenko S;Burnazi E;Ku A;Kalidindi T;Lee SG;Grkovski M;Beattie BJ;Zanzonico P;Lewis JS;Larson S;Rodina A;Pillarsetty N;Tabar V;Dunphy MP;Taldone T;Shimizu F;Chiosis G
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Chiosis G