title: Curcumin Pyrazole and its derivative (N-(3-Nitrophenylpyrazole) Curcumin inhibit aggregation, disrupt fibrils and modulate toxicity of Wild type and Mutant α-Synuclein.
abstract: Accumulating evidence suggests that deposition of neurotoxic α-synuclein aggregates in the brain during the development of neurodegenerative diseases like Parkinson's disease can be curbed by anti-aggregation strategies that either disrupt or eliminate toxic aggregates. Curcumin, a dietary polyphenol exhibits anti-amyloid activity but the use of this polyphenol is limited owing to its instability. As chemical modifications in curcumin confiscate this limitation, such efforts are intensively performed to discover molecules with similar but enhanced stability and superior properties. This study focuses on the inhibitory effect of two stable analogs of curcumin viz. curcumin pyrazole and curcumin isoxazole and their derivatives against α-synuclein aggregation, fibrillization and toxicity. Employing biochemical, biophysical and cell based assays we discovered that curcumin pyrazole (3) and its derivative N-(3-Nitrophenylpyrazole) curcumin (15) exhibit remarkable potency in not only arresting fibrillization and disrupting preformed fibrils but also preventing formation of A11 conformation in the protein that imparts toxic effects. Compounds 3 and 15 also decreased neurotoxicity associated with fast aggregating A53T mutant form of α-synuclein. These two analogues of curcumin described here may therefore be useful therapeutic inhibitors for the treatment of α-synuclein amyloidosis and toxicity in Parkinson's disease and other synucleinopathies.
authors.affiliation: Molecular Science Lab, National Institute of Immunology, New Delhi, INDIA 110067.
authors.forename: Nuzhat
authors.initials: N
authors.lastname: Ahsan
authors.affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore, INDIA 560012.
authors.forename: Satyendra
authors.initials: S
authors.lastname: Mishra
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi, INDIA 110067.
authors.forename: Manish Kumar
authors.initials: MK
authors.lastname: Jain
authors.affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore, INDIA 560012.
authors.forename: Avadhesha
authors.initials: A
authors.lastname: Surolia
authors.affiliation: Molecular Science Lab, National Institute of Immunology, New Delhi, INDIA 110067.
authors.forename: Sarika
authors.initials: S
authors.lastname: Gupta
mesh_terms: D003474:Curcumin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects; D013329:Structure-Activity Relationship; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D051844:alpha-Synuclein; D003474:Curcumin