Structure-activity relationships of flurbiprofen analogues as stabilizers of the amyloidogenic protein transthyretin

doi:10.1016/j.jsb.2019.08.011

	Structure-activity relationships of flurbiprofen analogues as stabilizers of the amyloidogenic protein transthyretin
	Loconte, Valentina1,5 ; Menozzi, Ilaria 2; Ferrari, Alberto 3; Folli, Claudia 3; Imbimbo, Bruno P.4; Zanotti, Giuseppe 1; Berni, Rodolfo 2
	2019-11
发表期刊	JOURNAL OF STRUCTURAL BIOLOGY (IF:3.0[JCR-2023],2.5[5-Year])
ISSN	1047-8477
EISSN	1095-8657
卷号	208 期号:2 页码:165-173
发表状态	已发表
DOI	10.1016/j.jsb.2019.08.011
摘要	The inherent amyloidogenic potential of wild type transthyretin (TTR) is enhanced by a large number of point mutations, which destabilize the TTR tetramer, thereby promoting its disassembly and pathological aggregation responsible for TTR-related amyloidosis. TTR stabilizers are able to interact with the thyroxine-binding sites of TTR, stabilizing its tetrameric native state and inhibiting amyloidogenesis. Herein, we report on in vitro, ex vivo, and X-ray analyses to assess the TTR structural stabilization by analogues of flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID). Overall, considering together binding selectivity and protective effects on TTR native structure by flurbiprofen analogues in the presence of plasma proteins, as determined by Western Blot, the aforementioned properties of analyzed compounds appear to be better (CHF5075 and CHF4802) or similar (CHF4795) or worse (CHF5074, also known as CSP-1103) as compared to those of diflunisal, used as a reference TTR stabilizer. Molecular details of the determinants affecting the interactions of CHF5075, CHF4802, and CHF4795 with wild type TTR and of CHF5074 with the amyloidogenic A25T TTR variant have been elucidated by X-ray analysis. Distinct interactions with TTR appear to characterize flurbiprofen analogues and the NSAID diflunisal and its analogues as TTR stabilizers. Relationships between stabilizing effect on TTR by flurbiprofen analogues determined experimentally and molecular details of their interactions with TTR have been established, providing the rationale for their protective effects on the native protein structure.
关键词	Amyloidogenic proteins Transthyretin Amyloidogenesis inhibitors Transthyretin stabilizers Ligand binding design
收录类别	SCI ; SCIE
语种	英语
资助项目	PRIN (Progetti di Rilevante Interesse Nazionale, MIUR, Rome, Italy) Project[2012A7LMS3_002]
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
WOS类目	Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
WOS记录号	WOS:000494503600010
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
WOS关键词	NATIVE-STATE STABILIZATION ; RETINOL-BINDING-PROTEIN ; DISEASE ; CHF5074 ; POTENT ; DIFLUNISAL ; TAFAMIDIS ; VARIANTS ; MODEL
原始文献类型	Article
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/102266
专题	iHuman研究所_特聘教授组_Andrej Sali组
通讯作者	Zanotti, Giuseppe; Berni, Rodolfo
作者单位	1.Univ Padua, Dept Biomed Sci, I-35131 Padua, Italy 2.Univ Parma, Dept Chem Life Sci & Environm Sustainabil, I-43124 Parma, Italy 3.Univ Parma, Dept Food & Drug, I-43124 Parma, Italy 4.Chiesi Farmaceut, Res & Dev, I-43122 Parma, Italy 5.ShanghaiTech Univ, iHuman Inst, Shanghai, Pudong, Peoples R China
第一作者单位	iHuman研究所
推荐引用方式 GB/T 7714	Loconte, Valentina,Menozzi, Ilaria,Ferrari, Alberto,et al. Structure-activity relationships of flurbiprofen analogues as stabilizers of the amyloidogenic protein transthyretin[J]. JOURNAL OF STRUCTURAL BIOLOGY,2019,208(2):165-173.
APA	Loconte, Valentina.,Menozzi, Ilaria.,Ferrari, Alberto.,Folli, Claudia.,Imbimbo, Bruno P..,...&Berni, Rodolfo.(2019).Structure-activity relationships of flurbiprofen analogues as stabilizers of the amyloidogenic protein transthyretin.JOURNAL OF STRUCTURAL BIOLOGY,208(2),165-173.
MLA	Loconte, Valentina,et al."Structure-activity relationships of flurbiprofen analogues as stabilizers of the amyloidogenic protein transthyretin".JOURNAL OF STRUCTURAL BIOLOGY 208.2(2019):165-173.