Protein aggregation-inhibition: a therapeutic route from Parkinson's disease to sickle cell anemia.

IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Gabriel F Martins, N Galamba
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引用次数: 2

Abstract

Protein aggregation is implicated in multiple diseases, so-called proteinopathies, ranging from neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease (PD) to type 2 diabetes mellitus and sickle cell disease (SCD). The structure of the protein aggregates and the kinetics and mechanisms of aggregation have been the object of intense research over the years toward the development of therapeutic routes, including the design of aggregation inhibitors. Nonetheless, the rational design of drugs targeting aggregation inhibition remains a challenging endeavor because of multiple, disease-specific factors, including an incomplete understanding of protein function, the multitude of toxic and non-toxic protein aggregates, the lack of specific drug binding targets, discrepant action mechanisms of aggregation inhibitors, or a low selectivity, specificity, and/or drug potency, reflected in the high concentrations required for some inhibitors to be effective. Herein, we provide a perspective of this therapeutic route with emphasis on small molecules and peptide-based drugs in two diverse diseases, PD and SCD, aiming at establishing links among proposed aggregation inhibitors. The small and large length-scale regimes of the hydrophobic effect are discussed in light of the importance of hydrophobic interactions in proteinopathies. Some simulation results are reported on model peptides, illustrating the impact of hydrophobic and hydrophilic groups in water's hydrogen-bond network with an impact on drug binding. The seeming importance of aromatic rings and hydroxyl groups in protein-aggregation-inhibitor-drugs is emphasized along with the challenges associated with some inhibitors, limiting their development into effective therapeutic options, and questioning the potential of this therapeutic route.

蛋白聚集抑制:从帕金森病到镰状细胞性贫血的治疗途径。
蛋白质聚集与多种疾病有关,即所谓的蛋白质病变,从阿尔茨海默病和帕金森病(PD)等神经退行性疾病到2型糖尿病和镰状细胞病(SCD)。多年来,蛋白质聚集体的结构、聚集的动力学和机制一直是研究的重点,旨在开发治疗途径,包括设计聚集抑制剂。尽管如此,合理设计靶向聚集抑制的药物仍然是一项具有挑战性的努力,因为多种疾病特异性因素,包括对蛋白质功能的不完全了解,大量有毒和无毒蛋白质聚集体,缺乏特异性药物结合靶点,聚集抑制剂的作用机制不一致,或低选择性,特异性和/或药物效力。反映在一些抑制剂需要高浓度才能有效。在此,我们提供了这一治疗途径的观点,重点是小分子和基于肽的药物在两种不同的疾病,PD和SCD,旨在建立拟议的聚集抑制剂之间的联系。鉴于疏水相互作用在蛋白质病变中的重要性,讨论了疏水效应的小尺度和大尺度机制。本文报道了一些模型肽的模拟结果,说明了水的氢键网络中疏水和亲水基团对药物结合的影响。在蛋白质聚集抑制剂药物中,芳香族环和羟基的重要性与一些抑制剂相关的挑战一起被强调,限制了它们发展成为有效的治疗选择,并质疑这种治疗途径的潜力。
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来源期刊
CiteScore
14.90
自引率
0.00%
发文量
6
期刊介绍: As the discipline of biochemistry and molecular biology have greatly advanced in the last quarter century, significant contributions have been made towards the advancement of general medicine, genetics, immunology, developmental biology, and biophysics. Investigators in a wide range of disciplines increasingly require an appreciation of the significance of current biochemical and molecular biology advances while, members of the biochemical and molecular biology community itself seek concise information on advances in areas remote from their own specialties. Critical Reviews in Biochemistry and Molecular Biology believes that well-written review articles prove an effective device for the integration and meaningful comprehension of vast, often contradictory, literature. Review articles also provide an opportunity for creative scholarship by synthesizing known facts, fruitful hypotheses, and new concepts. Accordingly, Critical Reviews in Biochemistry and Molecular Biology publishes high-quality reviews that organize, evaluate, and present the current status of high-impact, current issues in the area of biochemistry and molecular biology. Topics are selected on the advice of an advisory board of outstanding scientists, who also suggest authors of special competence. The topics chosen are sufficiently broad to interest a wide audience of readers, yet focused enough to be within the competence of a single author. Authors are chosen based on their activity in the field and their proven ability to produce a well-written publication.
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