The structural and functional dynamics of BiP and Grp94: opportunities for therapeutic discovery.

IF 19.9 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Trends in pharmacological sciences Pub Date : 2025-05-01 Epub Date: 2025-04-18 DOI:10.1016/j.tips.2025.03.004
Ikponwmosa Obaseki, Chioma C Ndolo, Ayodeji A Adedeji, Hannah O Popoola, Andrea N Kravats
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引用次数: 0

Abstract

Binding immunoglobulin protein (BiP) and glucose-regulated protein 94 (Grp94) are endoplasmic reticulum (ER)-localized molecular chaperones that ensure proper protein folding and maintain protein homeostasis. However, overexpression of these chaperones during ER stress can contribute to disease progression in numerous pathologies. Although these chaperones represent promising therapeutic targets, their inhibition has been challenged by gaps in understanding of targetable chaperone features and their complex biology. To overcome these challenges, a new assay has been developed to selectively target BiP, and compounds that exploit subtle conformational changes of Grp94 have been designed. This review summarizes recent advances in elucidating structural and functional dynamics of BiP and Grp94. We explore leveraging this information to develop novel therapeutic interventions. Finally, given the recent advances in computing, we discuss how machine learning methods can be used to accelerate drug discovery efforts.

BiP和Grp94的结构和功能动力学:治疗发现的机会。
结合免疫球蛋白蛋白(BiP)和葡萄糖调节蛋白94 (Grp94)是内质网(ER)定位的分子伴侣,确保适当的蛋白质折叠和维持蛋白质稳态。然而,内质网应激过程中这些伴侣蛋白的过度表达可导致多种病理的疾病进展。尽管这些伴侣蛋白代表了有希望的治疗靶点,但由于对靶向伴侣蛋白特征及其复杂生物学的了解不足,它们的抑制作用受到了挑战。为了克服这些挑战,研究人员开发了一种新的方法来选择性地靶向BiP,并设计了利用Grp94细微构象变化的化合物。本文综述了近年来在阐明BiP和Grp94的结构和功能动力学方面的进展。我们探索利用这些信息来开发新的治疗干预措施。最后,鉴于计算机的最新进展,我们讨论了如何使用机器学习方法来加速药物发现工作。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
23.90
自引率
0.70%
发文量
132
审稿时长
6-12 weeks
期刊介绍: Trends in Pharmacological Sciences (TIPS) is a monthly peer-reviewed reviews journal that focuses on a wide range of topics in pharmacology, pharmacy, pharmaceutics, and toxicology. Launched in 1979, TIPS publishes concise articles discussing the latest advancements in pharmacology and therapeutics research. The journal encourages submissions that align with its core themes while also being open to articles on the biopharma regulatory landscape, science policy and regulation, and bioethics. Each issue of TIPS provides a platform for experts to share their insights and perspectives on the most exciting developments in the field. Through rigorous peer review, the journal ensures the quality and reliability of published articles. Authors are invited to contribute articles that contribute to the understanding of pharmacology and its applications in various domains. Whether it's exploring innovative drug therapies or discussing the ethical considerations of pharmaceutical research, TIPS provides a valuable resource for researchers, practitioners, and policymakers in the pharmacological sciences.
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