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Synthesis and Preliminary Characterization of Putative Anle138b-Centered PROTACs against α-Synuclein Aggregation.

ABSTRACT: The search for disease-modifying agents targeted against Parkinson's disease led us to rationally design a small array of six Anle138b-centered PROTACs, 7a,b, 8a,b and 9a,b, targeting αSynuclein (αSyn) aggregates for binding, polyubiquitination by the E3 ligase Cereblon (CRBN), and proteasomal degradation. Lenalidomide and thalidomide were used as CRBN ligands and coupled with amino- and azido Anle138b derivatives through flexible linkers and coupling reactions (amidation, 'click' chemistry). Four Anle138b-PROTACs, 8a,b and 9a,b, were characterized against in vitro αSyn aggregation, monitoring them in a Thioflavin T (ThT) fluorescence assay and in dopaminergic neurons derived from a set of isogenic pluripotent stem cell (iPSC) lines with SNCA multiplications. Native and seeded αSyn aggregation was determined with a new biosensor, and a partial correlation between αSyn aggregation, cellular dysfunctions, and neuronal survival was obtained. Anle138b-PROTAC 8a was characterized as the most promising αSyn aggregation inhibitor/degradation inducer, with potential usefulness against synucleinopathies and cancer.

SUBMITTER: Pedrini M

PROVIDER: S-EPMC10221781 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Synthesis and Preliminary Characterization of Putative Anle138b-Centered PROTACs against α-Synuclein Aggregation.

Pedrini Martina M Iannielli Angelo A Meneghelli Lorenzo L Passarella Daniele D Broccoli Vania V Seneci Pierfausto P

Pharmaceutics 20230511 5

The search for disease-modifying agents targeted against Parkinson's disease led us to rationally design a small array of six Anle138b-centered PROTACs, 7a,b, 8a,b and 9a,b, targeting αSynuclein (αSyn) aggregates for binding, polyubiquitination by the E3 ligase Cereblon (CRBN), and proteasomal degradation. Lenalidomide and thalidomide were used as CRBN ligands and coupled with amino- and azido Anle138b derivatives through flexible linkers and coupling re ...[more]

PMID: 37242709

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Project description:Methamphetamine (METH) is an illegal and widely abused psychoactive stimulant. METH abusers are at high risk of neurodegenerative disorders, including Parkinson's disease (PD). Previous studies have demonstrated that METH causes alpha-synuclein (α-syn) aggregation in the both laboratory animal and human. In this study, exposure to high METH doses increased the expression of α-syn and the small ubiquitin-related modifier 1 (SUMO-1). Therefore, we hypothesized that SUMOylation of α-syn is involved in high-dose METH-induced α-syn aggregation. We measured the levels of α-syn SUMOylation and these enzymes involved in the SUMOylation cycle in SH-SY5Y human neuroblastoma cells (SH-SY5Y cells), in cultures of C57 BL/6 primary mouse neurons and in brain tissues of mice exposure to METH. We also demonstrated the effect of α-syn SUMOylation on α-syn aggregation after METH exposure by overexpressing the key enzyme of the SUMOylation cycle or silencing SUMO-1 expression in vitro. Then, we make introduced mutations in the major SUMOylation acceptor sites of α-syn by transfecting a lentivirus containing the sequence of WT α-syn or K96/102R α-syn into SH-SY5Y cells and injecting an adenovirus containing the sequence of WT α-syn or K96/102R α-syn into the mouse striatum. Levels of the ubiquitin-proteasome system (UPS)-related makers ubiquitin (Ub) and UbE1, as well as the autophagy-lysosome pathway (ALP)-related markers LC3, P62 and lysosomal associated membrane protein 2A (LAMP2A), were also measured in SH-SY5Y cells transfected with lentivirus and mice injected with adenovirus. The results showed that METH exposure decreases the SUMOylation level of α-syn, although the expression of α-syn and SUMO-1 are increased. One possible cause is the reduction of UBC9 level. The increase in α-syn SUMOylation by UBC9 overexpression relieves METH-induced α-syn overexpression and aggregation, whereas the decrease in α-syn SUMOylation by SUMO-1 silencing exacerbates the same pathology. Furthermore, mutations in the major SUMOylation acceptor sites of α-syn also aggravate α-syn overexpression and aggregation by impairing degradation through the UPS and the ALP in vitro and in vivo. These results suggest that SUMOylation of α-syn plays a fundamental part in α-syn overexpression and aggregation induced by METH and could be a suitable target for the treatment of neurodegenerative diseases.

Dataset Information

Synthesis and Preliminary Characterization of Putative Anle138b-Centered PROTACs against α-Synuclein Aggregation.

Publications

Synthesis and Preliminary Characterization of Putative Anle138b-Centered PROTACs against α-Synuclein Aggregation.

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