Chemical kinetics for drug discovery to combat protein aggregation diseases

被引:189
作者
Arosio, Paolo [1 ]
Vendruscolo, Michele [1 ]
Dobson, Christopher M. [1 ]
Knowles, Tuomas P. J. [1 ]
机构
[1] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England
基金
英国生物技术与生命科学研究理事会;
关键词
inhibition mechanism; neurodegenerative diseases; therapeutics; aggregation kinetics; AMYLOID-BETA-PROTEIN; SICKLE HEMOGLOBIN POLYMERIZATION; ALPHA-B-CRYSTALLIN; NUCLEATION MECHANISM; MOLECULAR-MECHANISMS; ALZHEIMERS-DISEASE; FIBRIL FORMATION; CONGO RED; PEPTIDE; INHIBITORS;
D O I
10.1016/j.tips.2013.12.005
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Protein misfolding diseases are becoming increasingly prevalent, yet there are very few effective pharmacological treatments. The onset and progression of these diseases is associated with the aberrant aggregation of normally soluble proteins and peptides into amyloid fibrils. Because genetic and physiological findings suggest that protein aggregation is a key event in pathogenesis, an attractive therapeutic strategy against this class of disorders is the search for compounds able to interfere with this process, in particular by suppressing the formation of soluble toxic oligomeric aggregates. In this review, we discuss how chemical kinetics can contribute to the fundamental understanding of the molecular mechanism of aggregation, and speculate on the implications for the development of therapeutic molecules that inhibit specific steps in the aggregation pathway that are crucial for preventing toxicity.
引用
收藏
页码:127 / 135
页数:9
相关论文
共 79 条
[1]   Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly [J].
Abelein, Axel ;
Lang, Lisa ;
Lendel, Christofer ;
Graslund, Astrid ;
Danielsson, Jens .
FEBS LETTERS, 2012, 586 (22) :3991-3995
[2]  
Adamcik J, 2010, NAT NANOTECHNOL, V5, P423, DOI [10.1038/NNANO.2010.59, 10.1038/nnano.2010.59]
[3]   Protein aggregation diseases: pathogenicity and therapeutic perspectives [J].
Aguzzi, Adriano ;
O'Connor, Tracy .
NATURE REVIEWS DRUG DISCOVERY, 2010, 9 (03) :237-248
[4]   Time evolution of amyloid fibril length distribution described by a population balance model [J].
Arosio, Paolo ;
Beeg, Marten ;
Nicoud, Lucrece ;
Morbidelli, Massimo .
CHEMICAL ENGINEERING SCIENCE, 2012, 78 :21-32
[5]   Aggregation Stability of a Monoclonal Antibody During Downstream Processing [J].
Arosio, Paolo ;
Barolo, Giuliano ;
Mueller-Spaeth, Thomas ;
Wu, Hua ;
Morbidelli, Massimo .
PHARMACEUTICAL RESEARCH, 2011, 28 (08) :1884-1894
[6]   Insight into the kinetic of amyloid β(1-42) peptide self-aggregation:: Elucidation of inhibitors' mechanism of action [J].
Bartolini, Manuela ;
Bertucci, Carlo ;
Bolognesi, Maria Laura ;
Cavalli, Andrea ;
Melchiorre, Carlo ;
Andrisano, Vincenza .
CHEMBIOCHEM, 2007, 8 (17) :2152-2161
[7]   Strategies for the Inhibition of Protein Aggregation in Human Diseases [J].
Bartolini, Manuela ;
Andrisano, Vincenza .
CHEMBIOCHEM, 2010, 11 (08) :1018-1035
[8]   SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase [J].
Bennett, BL ;
Sasaki, DT ;
Murray, BW ;
O'Leary, EC ;
Sakata, ST ;
Xu, WM ;
Leisten, JC ;
Motiwala, A ;
Pierce, S ;
Satoh, Y ;
Bhagwat, SS ;
Manning, AM ;
Anderson, DW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (24) :13681-13686
[9]   Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils [J].
Bieschke, Jan ;
Herbst, Martin ;
Wiglenda, Thomas ;
Friedrich, Ralf P. ;
Boeddrich, Annett ;
Schiele, Franziska ;
Kleckers, Daniela ;
del Amo, Juan Miguel Lopez ;
Gruening, Bjoern A. ;
Wang, Qinwen ;
Schmidt, Michael R. ;
Lurz, Rudi ;
Anwyl, Roger ;
Schnoegl, Sigrid ;
Faendrich, Marcus ;
Frank, Ronald F. ;
Reif, Bernd ;
Guenther, Stefan ;
Walsh, Dominic M. ;
Wanker, Erich E. .
NATURE CHEMICAL BIOLOGY, 2012, 8 (01) :93-101
[10]   KINETICS OF NUCLEATION-CONTROLLED POLYMERIZATION - A PERTURBATION TREATMENT FOR USE WITH A SECONDARY PATHWAY [J].
BISHOP, MF ;
FERRONE, FA .
BIOPHYSICAL JOURNAL, 1984, 46 (05) :631-644