Sulfamerazine as a Potential Modulator against α-Synuclein Aggregation and Associated Toxicity

TY - JOUR

T1 - Sulfamerazine as a Potential Modulator against α-Synuclein Aggregation and Associated Toxicity

AU - Singh, Priyanka

AU - Kadam, Nagesh Y

AU - Panigrahi, Rajlaxmi

AU - Mehrotra, Arpit

AU - Upadhayay, Krishna

AU - Dey, Madhumita

AU - Tyagi, Arpit

AU - Aquib, Muhammad

AU - Nielsen, Janni

AU - Kleijwegt, Giulia

AU - Singh, Prashant

AU - Sharma, Abhishek

AU - Rao, Alka

AU - Otzen, Daniel E

AU - Kumar, Ashutosh

AU - Sharma, Deepak

PY - 2025/2/12

Y1 - 2025/2/12

N2 - Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. The presence of Lewy bodies, primarily consisting of amyloid aggregates of the protein α-synuclein (α-Syn), is a common feature seen in dopaminergic neurons in (PD) patients. In the present study, we screened 2320 FDA-approved drugs and found 3 lead molecules, sulfamerazine, lathosterol, and tamoxifen, that reproducibly inhibited α-Syn fibrillation. Dose-response studies showed that sulfamerazine and lathosterol are relatively more potent than tamoxifen in inhibiting α-Syn aggregation. Among the lead compounds, sulfamerazine showed a significant reduction in α-Syn aggregation and associated toxicity in Caenorhabditis elegans model of PD. Sulfamerazine also reduced the accumulation of α-Syn aggregates in neuronal SH-SY5Y cells. Microscale thermophoresis confirmed the binding of sulfamerazine to α-Syn. NMR studies corroborated the binding of sulfamerazine with α-Syn and show that upon interaction, α-Syn is sequestered into large soluble dispersed assemblies, which is similar to as seen in transmission electron microscopy. We conclude that sulfamerazine and its derivatives hold promise as therapeutic agents against Parkinson's disease.

AB - Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. The presence of Lewy bodies, primarily consisting of amyloid aggregates of the protein α-synuclein (α-Syn), is a common feature seen in dopaminergic neurons in (PD) patients. In the present study, we screened 2320 FDA-approved drugs and found 3 lead molecules, sulfamerazine, lathosterol, and tamoxifen, that reproducibly inhibited α-Syn fibrillation. Dose-response studies showed that sulfamerazine and lathosterol are relatively more potent than tamoxifen in inhibiting α-Syn aggregation. Among the lead compounds, sulfamerazine showed a significant reduction in α-Syn aggregation and associated toxicity in Caenorhabditis elegans model of PD. Sulfamerazine also reduced the accumulation of α-Syn aggregates in neuronal SH-SY5Y cells. Microscale thermophoresis confirmed the binding of sulfamerazine to α-Syn. NMR studies corroborated the binding of sulfamerazine with α-Syn and show that upon interaction, α-Syn is sequestered into large soluble dispersed assemblies, which is similar to as seen in transmission electron microscopy. We conclude that sulfamerazine and its derivatives hold promise as therapeutic agents against Parkinson's disease.

KW - Caenorhabditis elegans model of PD

KW - Parkinson’s disease

KW - SH-SY5Y cells

KW - amyloid aggregates

KW - sulfamerazine

KW - α-synuclein

UR - http://www.scopus.com/inward/record.url?scp=85217521474&partnerID=8YFLogxK

U2 - 10.1021/acschemneuro.4c00803

DO - 10.1021/acschemneuro.4c00803

M3 - Journal article

C2 - 39936279

SN - 1948-7193

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

ER -