Oxysterole-Binding Protein targeted by SARS-CoV-2 Viral Proteins regulates Coronavirus Replication Provisionally Accepted
Yue Ma-Lauer1
Pengyuan Li1
Daniela Niemeyer2
Anja Richter2
Konstantin Pusl1
Brigitte von Brunn1
Yi Ru1
Chengyu Xiang1
Sebastian Schwinghammer1
Jia Liu1
Priya Baral1
Emilia Berthold1
Haibo Qiu3
Avishek Roy3
Elisabeth Kremmer4
Heinrich Flaswinkel4
Christian Drosten2
Zhendong Jin3
Albrecht von Brunn1*
- 1Max von Pettenkofer Institute, Dep. of Virology, Faculty of Medicine, LMU Munich; German Center for Infection Research (DZIF), Munich site, Germany
- 2Institute of Virology, Charité Medical University of Berlin, Germany
- 3Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, The University of Iowa, United States
- 4BioSysM, Ludwig-Maximilians-University Munich, Munich, Germany, Germany
Oxysterol-binding protein (OSBP) functions as a critical lipid transporter, facilitating the exchange of cholesterol between the Golgi apparatus and endoplasmic reticulum membranes.We show that OSBP plays a critical role in the positive regulation of coronavirus replication. In addition, we introduce a novel OSBP-binding compound, ZJ-1, which reduces OSBP levels and exhibits potent antiviral effects against several coronaviruses, including SARS-CoV-2. Through our investigation, we identified the SARS-CoV-2 non-structural proteins Nsp3, Nsp4, and Nsp6as key interactors with OSBP, particularly involved in double-membrane vesicle formation. In addition, Nsp3 a.a.1-1363, Nsp4, and Nsp6 target vesicle-associated membrane protein (VAMP)-associated protein B (VAP-B), a critical factor in anchoring OSBP to the ER membrane.Notably, the interaction between OSBP and VAP-B is substantially disrupted by Nsp3 a.a.1-1363 and partially impaired by Nsp6. Furthermore, SARS-CoV-2 orf7a, orf7b, and orf3a were identified as additional OSBP targets, with OSBP contributing to their stabilization. Our findings highlight OSBP as a promising target for the development of antiviral therapies against SARS-CoV-2 and other coronaviruses.
Keywords: OSBP, SARS-CoV-2, Coronavirus, Nsp3, NSP4, NSP6, VAP-B
Received: 08 Feb 2024;
Accepted: 09 May 2024.
Copyright: © 2024 Ma-Lauer, Li, Niemeyer, Richter, Pusl, von Brunn, Ru, Xiang, Schwinghammer, Liu, Baral, Berthold, Qiu, Roy, Kremmer, Flaswinkel, Drosten, Jin and von Brunn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Albrecht von Brunn, Max von Pettenkofer Institute, Dep. of Virology, Faculty of Medicine, LMU Munich; German Center for Infection Research (DZIF), Munich site, Munich, Bavaria, Germany