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高特异性西格玛受体配体在感染新冠病毒的细胞中展现出抗病毒特性。

Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells.

作者信息

Ostrov David A, Bluhm Andrew P, Li Danmeng, Khan Juveriya Qamar, Rohamare Megha, Rajamanickam Karthic, K Bhanumathy Kalpana, Lew Jocelyne, Falzarano Darryl, Vizeacoumar Franco J, Wilson Joyce A, Mottinelli Marco, Kanumuri Siva Rama Raju, Sharma Abhisheak, McCurdy Christopher R, Norris Michael H

机构信息

Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.

Department of Geography, University of Florida College of Liberal Arts and Sciences, Gainesville, FL 32611, USA.

出版信息

Pathogens. 2021 Nov 20;10(11):1514. doi: 10.3390/pathogens10111514.

DOI:10.3390/pathogens10111514
PMID:34832669
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8620039/
Abstract

(1) Background: There is a strong need for prevention and treatment strategies for COVID-19 that are not impacted by SARS-CoV-2 mutations emerging in variants of concern. After virus infection, host ER resident sigma receptors form direct interactions with non-structural SARS-CoV-2 proteins present in the replication complex. (2) Methods: In this work, highly specific sigma receptor ligands were investigated for their ability to inhibit both SARS-CoV-2 genome replication and virus induced cellular toxicity. This study found antiviral activity associated with agonism of the sigma-1 receptor (e.g., SA4503), ligation of the sigma-2 receptor (e.g., CM398), and a combination of the two pathways (e.g., AZ66). (3) Results: Intermolecular contacts between these ligands and sigma receptors were identified by structural modeling. (4) Conclusions: Sigma receptor ligands and drugs with off-target sigma receptor binding characteristics were effective at inhibiting SARS-CoV-2 infection in primate and human cells, representing a potential therapeutic avenue for COVID-19 prevention and treatment.

摘要

（1）背景：迫切需要针对新冠病毒（COVID-19）的预防和治疗策略，这些策略不受关注变异株中出现的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）突变的影响。病毒感染后，宿主内质网驻留西格玛受体与复制复合物中存在的非结构SARS-CoV-2蛋白形成直接相互作用。（2）方法：在本研究中，研究了高特异性西格玛受体配体抑制SARS-CoV-2基因组复制和病毒诱导的细胞毒性的能力。该研究发现抗病毒活性与西格玛-1受体激动作用（如SA4503）、西格玛-2受体结合（如CM398）以及两种途径的组合（如AZ66）相关。（3）结果：通过结构建模确定了这些配体与西格玛受体之间的分子间接触。（4）结论：西格玛受体配体和具有脱靶西格玛受体结合特性的药物在抑制灵长类和人类细胞中的SARS-CoV-2感染方面有效，代表了一种潜在的COVID-19预防和治疗途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/f9dd4f8daf72/pathogens-10-01514-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/da1e80be2f01/pathogens-10-01514-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/ebc2653f9999/pathogens-10-01514-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/c2d81ec7c6a4/pathogens-10-01514-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/754047ed91bf/pathogens-10-01514-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/d2bde16dec4d/pathogens-10-01514-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/ff1497151d8f/pathogens-10-01514-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/a2567ea36ce5/pathogens-10-01514-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/45496c6e253d/pathogens-10-01514-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/f9dd4f8daf72/pathogens-10-01514-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/da1e80be2f01/pathogens-10-01514-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/ebc2653f9999/pathogens-10-01514-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/c2d81ec7c6a4/pathogens-10-01514-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/754047ed91bf/pathogens-10-01514-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/d2bde16dec4d/pathogens-10-01514-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/ff1497151d8f/pathogens-10-01514-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/a2567ea36ce5/pathogens-10-01514-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/45496c6e253d/pathogens-10-01514-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dce/8620039/f9dd4f8daf72/pathogens-10-01514-g009.jpg

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