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Development of sigma-1 (?1) receptor fluorescent ligands as versatile tools to study ?1 receptors.

ABSTRACT: Despite their controversial physiology, sigma-1 (?1) receptors are intriguing targets for the development of therapeutic agents for central nervous system diseases. With the aim of providing versatile pharmacological tools to study ?1 receptors, we developed three ?1 fluorescent tracers by functionalizing three well characterized ?1 ligands with a fluorescent tag. A good compromise between ?1 binding affinity and fluorescent properties was reached, and the ?1 specific targeting of the novel tracers was demonstrated by confocal microscopy and flow cytometry. These novel ligands were also successfully used in competition binding studies by flow cytometry, showing their utility in nonradioactive binding assays as an alternative strategy to the more classical radioligand binding assays. To the best of our knowledge these are the first ?1 fluorescent ligands to be developed and successfully employed in living cells, representing promising tools to strengthen ?1 receptors related studies.

SUBMITTER: Abate C

PROVIDER: S-EPMC4755300 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Development of sigma-1 (σ1) receptor fluorescent ligands as versatile tools to study σ1 receptors.

Abate Carmen C Riganti Chiara C Pati Maria Laura ML Ghigo Dario D Berardi Francesco F Mavlyutov Timur T Guo Lian-Wang LW Ruoho Arnold A

European journal of medicinal chemistry 20151213

Despite their controversial physiology, sigma-1 (σ1) receptors are intriguing targets for the development of therapeutic agents for central nervous system diseases. With the aim of providing versatile pharmacological tools to study σ1 receptors, we developed three σ1 fluorescent tracers by functionalizing three well characterized σ1 ligands with a fluorescent tag. A good compromise between σ1 binding affinity and fluorescent properties was reached, and the σ1 specific targeting of the novel trac ...[more]

PMID: 26717207

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Project description: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.

Dataset Information

Development of sigma-1 (?1) receptor fluorescent ligands as versatile tools to study ?1 receptors.

Publications

Development of sigma-1 (σ1) receptor fluorescent ligands as versatile tools to study σ1 receptors.

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