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Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays.

ABSTRACT: The sigma 1 receptor (?1R) is a structurally unique transmembrane protein that functions as a molecular chaperone in the endoplasmic reticulum (ER), and has been implicated in cancer, neuropathic pain, and psychostimulant abuse. Despite physiological and pharmacological significance, mechanistic underpinnings of structure-function relationships of ?1R are poorly understood, and molecular interactions of selective ligands with ?1R have not been elucidated. The recent crystallographic determination of ?1R as a homo-trimer provides the foundation for mechanistic elucidation at the molecular level. Here we report novel bioluminescence resonance energy transfer (BRET) assays that enable analyses of ligand-induced multimerization of ?1R and its interaction with BiP. Haloperidol, PD144418, and 4-PPBP enhanced ?1R homomer BRET signals in a dose dependent manner, suggesting their significant effects in stabilizing ?1R multimerization, whereas (+)-pentazocine and several other ligands do not. In non-denaturing gels, (+)-pentazocine significantly decreased whereas haloperidol increased the fraction of ?1R multimers, consistent with the results from the homomer BRET assay. Further, BRET assays examining heteromeric ?1R-BiP interaction revealed that (+)-pentazocine and haloperidol induced opposite trends of signals. From molecular modeling and simulations of ?1R in complex with the tested ligands, we identified initial clues that may lead to the differed responses of ?1R upon binding of structurally diverse ligands. By combining multiple in vitro pharmacological and in silico molecular biophysical methods, we propose a novel integrative approach to analyze ?1R-ligand binding and its impact on interaction of ?1R with client proteins.

SUBMITTER: Yano H

PROVIDER: S-EPMC5858991 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays.

Yano Hideaki H Bonifazi Alessandro A Xu Min M Guthrie Daryl A DA Schneck Stephanie N SN Abramyan Ara M AM Fant Andrew D AD Hong W Conrad WC Newman Amy H AH Shi Lei L

Neuropharmacology 20180131

The sigma 1 receptor (σ1R) is a structurally unique transmembrane protein that functions as a molecular chaperone in the endoplasmic reticulum (ER), and has been implicated in cancer, neuropathic pain, and psychostimulant abuse. Despite physiological and pharmacological significance, mechanistic underpinnings of structure-function relationships of σ1R are poorly understood, and molecular interactions of selective ligands with σ1R have not been elucidated. The rec ...[more]

PMID: 29407216

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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

Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays.

Publications

Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays.

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