Interactions of tolcapone analogues as stabilizers of the amyloidogenic protein transthyretin

doi:10.1016/j.bioorg.2020.104144

	Interactions of tolcapone analogues as stabilizers of the amyloidogenic protein transthyretin
	Loconte, Valentina1 ; Cianci, Michele 2; Menozzi, Ilaria 3; Sbravati, Davide 3; Sansone, Francesco 3; Casnati, Alessandro 3; Berni, Rodolfo 3
	2020-10
发表期刊	BIOORGANIC CHEMISTRY (IF:4.5[JCR-2023],4.7[5-Year])
ISSN	0045-2068
卷号	103
DOI	10.1016/j.bioorg.2020.104144
摘要	Transthyretin (TTR) is an amyloidogenic homotetramer involved in the transport of thyroxine and retinol in blood and cerebrospinal fluid. TTR stabilizers, such as tolcapone, an FDA approved drug for Parkinson's disease, are able to interact with residues of the thyroxine-binding sites of TTR, both wild type and pathogenic mutant forms, thereby stabilizing its tetrameric native state and inhibiting amyloidogenesis. Herein, we report on the synthesis of 3-deoxytolcapone, a novel stabilizer of TTR. The high-resolution X-ray analyses of the interactions of 3-O-methyltolcapone and 3-deoxytolcapone with TTR were performed. In the two TTR - ligand complexes the tolcapone analogues establish mainly H-bond and hydrophobic interactions with residues of the thyroxine-binding site of the TTR tetramer. Both compounds are capable of high and selective stabilization of TTR in the presence of plasma proteins, despite their markedly different 'forward' and 'reverse' binding mode, respectively. In fact, the loss or the weakening of stabilizing interactions with protein residues of 3-deoxytolcapone in comparison with tolcapone and 3-O-methyltolcapone is compensated by new interactions established at the dimer-dimer interface. Our data, coupled with previously reported data on the pharmacokinetics properties in humans of tolcapone and 3-O-methyltolcapone, further support the relevance of the latter tolcapone analogue as TTR stabilizer.
关键词	Amyloidogenic proteins Transthyretin Amyloidogenesis inhibitors Transthyretin stabilizers Structure-activity relationships Tolcapone analogues
收录类别	SCI ; SCIE
语种	英语
资助项目	PRIN Projects (Progetti di Rilevante Interesse Nazionale) of the Italian Ministry of Education, University and Research (MIUR, Rome, Italy)[2012A7LMS3_002][2017E44A9P]
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
WOS类目	Biochemistry & Molecular Biology ; Chemistry, Organic
WOS记录号	WOS:000575790500008
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/123513
专题	iHuman研究所_特聘教授组_Andrej Sali组
通讯作者	Sansone, Francesco; Berni, Rodolfo
作者单位	1.ShanghaiTech Univ, iHuman Inst, Pudong 201210, Peoples R China; 2.Polytech Univ Marche, Dept Agr Food & Environm Sci, I-60131 Ancona, Italy; 3.Univ Parma, Dept Chem Life Sci & Environm Sustainabil, I-43124 Parma, Italy
第一作者单位	iHuman研究所
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Loconte, Valentina,Cianci, Michele,Menozzi, Ilaria,et al. Interactions of tolcapone analogues as stabilizers of the amyloidogenic protein transthyretin[J]. BIOORGANIC CHEMISTRY,2020,103.
APA	Loconte, Valentina.,Cianci, Michele.,Menozzi, Ilaria.,Sbravati, Davide.,Sansone, Francesco.,...&Berni, Rodolfo.(2020).Interactions of tolcapone analogues as stabilizers of the amyloidogenic protein transthyretin.BIOORGANIC CHEMISTRY,103.
MLA	Loconte, Valentina,et al."Interactions of tolcapone analogues as stabilizers of the amyloidogenic protein transthyretin".BIOORGANIC CHEMISTRY 103(2020).