PXD036283-2

PXD036283 is an original dataset announced via ProteomeXchange.

Title	Repurposing of Amisulpride, a known antipsychotic drug, to target synovial fibroblasts activation in arthritis.
Description	Synovial Fibroblasts (SFs) are key pathogenic drivers in arthritis and their in vivo activation by TNF is sufficient to orchestrate full arthritic pathogenesis in animal models. TNF blockade has been efficacious for a large percentage of Rheumatoid Arthritis (RA) patients, although characterized by a plethora of side effects. Novel therapeutic discoveries remain however challenging, especially in optimizing drug safety, side effects, longer-term responses, costs and administration routes. Aiming to find new potent therapeutics, we applied the L1000CDS2 search engine, in order to identify compounds that could potentially reverse the pathogenic expression signature of arthritogenic SFs, derived from the human TNF transgenic mouse model (hTNFtg). We identified a neuroleptic drug, namely Amisulpride, which was validated to reduce SFs’ inflammatory potential while decreasing the clinical score of hTNFtg polyarthritis. Notably, we found that Amisulpride did not exert its biological activities through its known targets Dopamine receptors 2 and 3 and Serotonin Receptor 7, nor through TNFTNFRI binding inhibition. By applying a click chemistry approach, novel potential targets of Amisulpride were identified, which were further validated to repress hTNFtg SFs’ inflammatory potential in vitro (Ascc3 and Sec62), while phosphoproteomics analysis revealed important fibroblast activation pathways, such as adhesion, to be altered upon treatment. Our data support that Amisulpride could provide an additive beneficial effect to patients suffering from RA and comorbid dysthymia, as it may reduce SFs pathogenicity in parallel with its antidepressive activity. Importantly, Amisulpride may also serve as a “lead” compound for the development of novel, more potent therapeutics against chronic inflammatory diseases
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:58:04.002.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Martina Samiotaki
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-25 13:50:02	ID requested
1	2023-04-06 06:09:02	announced
⏵ 2	2023-11-14 08:58:04	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: Rheumatoid arthritis,Amisulpride, Repurposing, synovial fibroblasts, Chemical Proteomics, Click-Chemistry

George Kollias
contact affiliation	Institute for Bioinnovation, Biomedical Sciences Research Centre (B.S.R.C.) “Alexander Fleming”; Vari, Greece
contact email	kollias@fleming.gr
lab head
Martina Samiotaki
contact affiliation	Protein Analysis Laboratory B.S.R.C. "Alexander Fleming", Alexander Fleming Street 34 16672, Vari, Greece
contact email	samiotaki@fleming.gr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD036283
     1. Label: PRIDE project
     2. Name: Repurposing of Amisulpride, a known antipsychotic drug, to target synovial fibroblasts activation in arthritis.