scholarly journals Known Drugs Identified by Structure-Based Virtual Screening Are Able to Bind Sigma-1 Receptor and Increase Growth of Huntington Disease Patient-Derived Cells

2021 ◽  
Vol 22 (3) ◽  
pp. 1293
Author(s):  
Theo Battista ◽  
Gianmarco Pascarella ◽  
David Sasah Staid ◽  
Gianni Colotti ◽  
Jessica Rosati ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Huntington Disease ◽  
Drug Repositioning ◽  
3D Structure ◽  
Disease Patient ◽  
Neuroprotective Activity ◽  
Computational Docking ◽  
Sigma 1 Receptor ◽  
Sigma 1

Huntington disease (HD) is a devastating and presently untreatable neurodegenerative disease characterized by progressively disabling motor and mental manifestations. The sigma-1 receptor (σ1R) is a protein expressed in the central nervous system, whose 3D structure has been recently determined by X-ray crystallography and whose agonists have been shown to have neuroprotective activity in neurodegenerative diseases. To identify therapeutic agents against HD, we have implemented a drug repositioning strategy consisting of: (i) Prediction of the ability of the FDA-approved drugs publicly available through the ZINC database to interact with σ1R by virtual screening, followed by computational docking and visual examination of the 20 highest scoring drugs; and (ii) Assessment of the ability of the six drugs selected by computational analyses to directly bind purified σ1R in vitro by Surface Plasmon Resonance and improve the growth of fibroblasts obtained from HD patients, which is significantly impaired with respect to control cells. All six of the selected drugs proved able to directly bind purified σ1R in vitro and improve the growth of HD cells from both or one HD patient. These results support the validity of the drug repositioning procedure implemented herein for the identification of new therapeutic tools against HD.

Preliminary in vitro assessment of pharmacokinetic drug-drug interactions of EST64401 and EST64514, two sigma-1 receptor antagonists

Xenobiotica ◽  
2020 ◽  
pp. 1-40
Author(s):  
Raquel F. Reinoso ◽  
Sandra Yeste ◽  
Eva Ayet ◽  
María José Pretel ◽  
Ariadna Balada ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Receptor Antagonists ◽  
Sigma 1 Receptor ◽  
Sigma 1 ◽  
In Vitro Assessment ◽  
Pharmacokinetic Drug

scholarly journals The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

2017 ◽  
Vol 97 ◽  
pp. 46-59 ◽  
Author(s):  
Daniel Ryskamp ◽  
Jun Wu ◽  
Michal Geva ◽  
Rebecca Kusko ◽  
Iris Grossman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington Disease ◽  
Sigma 1 Receptor ◽  
Beneficial Effects ◽  
Sigma 1

scholarly journals Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?

2020 ◽  
Vol 11 ◽  
Author(s):  
José Miguel Vela
Keyword(s):  
Stress Response ◽  
Viral Replication ◽  
Er Stress ◽  
Host Cell ◽  
Drug Repurposing ◽  
Host Protein ◽  
Unique Challenge ◽  
Sigma 1 Receptor ◽  
Sigma 1

Outbreaks of emerging infections, such as COVID-19 pandemic especially, confront health professionals with the unique challenge of treating patients. With no time to discover new drugs, repurposing of approved drugs or in clinical development is likely the only solution. Replication of coronaviruses (CoVs) occurs in a modified membranous compartment derived from the endoplasmic reticulum (ER), causes host cell ER stress and activates pathways to facilitate adaptation of the host cell machinery to viral needs. Accordingly, modulation of ER remodeling and ER stress response might be pivotal in elucidating CoV-host interactions and provide a rationale for new therapeutic, host-based antiviral approaches. The sigma-1 receptor (Sig-1R) is a ligand-operated, ER membrane-bound chaperone that acts as an upstream modulator of ER stress and thus a candidate host protein for host-based repurposing approaches to treat COVID-19 patients. Sig-1R ligands are frequently identified in in vitro drug repurposing screens aiming to identify antiviral compounds against CoVs, including severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Sig-1R regulates key mechanisms of the adaptive host cell stress response and takes part in early steps of viral replication. It is enriched in lipid rafts and detergent-resistant ER membranes, where it colocalizes with viral replicase proteins. Indeed, the non-structural SARS-CoV-2 protein Nsp6 interacts with Sig-1R. The activity of Sig-1R ligands against COVID-19 remains to be specifically assessed in clinical trials. This review provides a rationale for targeting Sig-1R as a host-based drug repurposing approach to treat COVID-19 patients. Evidence gained using Sig-1R ligands in unbiased in vitro antiviral drug screens and the potential mechanisms underlying the modulatory effect of Sig-1R on the host cell response are discussed. Targeting Sig-1R is not expected to reduce dramatically established viral replication, but it might interfere with early steps of virus-induced host cell reprogramming, aid to slow down the course of infection, prevent the aggravation of the disease and/or allow a time window to mature a protective immune response. Sig-1R-based medicines could provide benefit not only as early intervention, preventive but also as adjuvant therapy.

scholarly journals N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jose A. Morales-Garcia ◽  
Javier Calleja-Conde ◽  
Jose A. Lopez-Moreno ◽  
Sandra Alonso-Gil ◽  
Marina Sanz-SanCristobal ◽  
...  
Keyword(s):  
Adult Neurogenesis ◽  
Spatial Learning And Memory ◽  
South American ◽  
New Production ◽  
Sigma 1 Receptor ◽  
Neurogenic Niche ◽  
Sigma 1 ◽  
Functional Relevance

Abstract N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.

scholarly journals Overexpression of sigma-1 receptor inhibits ADAM10 and ADAM17 mediated shedding in vitro

2012 ◽  
Vol 3 (2) ◽  
pp. 153-159 ◽  
Author(s):  
Juan Li ◽  
Bin Liu ◽  
Xiaofei Gao ◽  
Zhixing Ma ◽  
Tianyi CaoSong ◽  
...  
Keyword(s):  
Sigma 1 Receptor ◽  
Sigma 1

scholarly journals Erratum to: Overexpression of sigma-1 receptor inhibits ADAM10 and ADAM17 mediated shedding in vitro

2012 ◽  
Vol 3 (5) ◽  
pp. 400-400
Author(s):  
Juan Li ◽  
Bin Liu ◽  
Xiaofei Gao ◽  
Zhixing Ma ◽  
Tianyi CaoSong ◽  
...  
Keyword(s):  
Sigma 1 Receptor ◽  
Sigma 1

scholarly journals In vitro and in vivo sigma 1 receptor imaging studies in different disease states

2020 ◽  
Author(s):  
Hebaalla Agha ◽  
Christopher R. McCurdy
Keyword(s):  
Clinical Trials ◽  
Molecular Imaging ◽  
Receptor Imaging ◽  
Imaging Studies ◽  
Sigma 1 Receptor ◽  
The Road ◽  
Disease States ◽  
Sigma 1

Molecular imaging studies have paved the road for the development of successful σ1R ligands currently in clinical trials.

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