Antiviral Res. 2017 Dec;148:5-14. doi: 10.1016/j.antiviral.2017.10.016. Epub 2017 Oct 23.
Avasimibe: A novel hepatitis C virus inhibitor that targets the assembly of infectious viral particles
Longbo Hu 1, Jinqian Li 2, Hua Cai 3, Wenxia Yao 4, Jing Xiao 3, Yi-Ping Li 2, Xiu Qiu 5, Huimin Xia 6, Tao Peng 7
Direct-acting antivirals (DAAs), which target hepatitis C virus (HCV) proteins, have exhibited impressive efficacy in the management of chronic hepatitis C. However, the concerns regarding high costs, drug resistance mutations and subsequent unexpected side effects still call for the development of host-targeting agents (HTAs) that target host factors involved in the viral life cycle and exhibit pan-genotypic antiviral activity. Given the close relationship between lipid metabolism and the HCV life cycle, we investigated the anti-HCV activity of a series of lipid-lowering drugs that have been approved by government administrations or proven safety in clinical trials. Our results showed that avasimibe, an inhibitor of acyl coenzyme A:cholesterol acyltransferase (ACAT), exhibited marked pan-genotypic inhibitory activity and superior inhibition against HCV when combined with DAAs. Moreover, avasimibe significantly impaired the assembly of infectious HCV virions. Mechanistic studies demonstrated that avasimibe induced downregulation of microsomal triglyceride transfer protein expression, resulting in reduced apolipoprotein E and apolipoprotein B secretion. Therefore, the pan-genotypic antiviral activity and clinically proven safety endow avasimibe exceptional potential as a candidate for combination therapy with DAAs. In addition, the discovery of the antiviral properties of ACAT inhibitors also suggests that inhibiting the synthesis of cholesteryl esters might be an additional target for the therapeutic intervention for chronic HCV infection.
Am J Respir Cell Mol Biol. 2018 Dec;59(6):713-722. doi: 10.1165/rcmb.2017-0438OC.
Lanosterol Synthase Regulates Human Rhinovirus Replication in Human Bronchial Epithelial Cells
Christopher McCrae 1 2, Anatoly Dzgoev 1, Marcus Ståhlman 3, Jenny Horndahl 1, Rebecka Svärd 1, Arend Große 4, Theresia Großkopf 4, Mary-Ann Skujat 4, Nicola Williams 5, Steffen Schubert 4, Christophe Echeverri 6, Clive Jackson 5, Anabel Guedán 7, Roberto Solari 7, Outi Vaarala 1, Maarten Kraan 1, Madeleine Rådinger 2
Human rhinovirus (RV) infections are a significant risk factor for exacerbations of asthma and chronic obstructive pulmonary disease. Thus, approaches to prevent RV infection in such patients would give significant benefit. Through RNA interference library screening, we identified lanosterol synthase (LSS), a component of the cholesterol biosynthetic pathway, as a novel regulator of RV replication in primary normal human bronchial epithelial cells. Selective knock down of LSS mRNA with short interfering RNA inhibited RV2 replication in normal human bronchial epithelial cells. Small molecule inhibitors of LSS mimicked the effect of LSS mRNA knockdown in a concentration-dependent manner. We further demonstrated that the antiviral effect is not dependent on a reduction in total cellular cholesterol but requires a 24-hour preincubation with the LSS inhibitor. The rank order of antiviral potency of the LSS inhibitors used was consistent with LSS inhibition potency; however, all compounds showed remarkably higher potency against RV compared with the LSS enzyme potency. We showed that LSS inhibition led to an induction of 24(S),25 epoxycholesterol, an important regulator of the sterol pathway. We also demonstrated that LSS inhibition led to a profound increase in expression of the innate antiviral defense protein, IFN-β. We found LSS to be a novel regulator of RV replication and innate antiviral immunity and identified a potential molecular mechanism for this effect, via induction of 24(S),25 epoxycholesterol. Inhibition of LSS could therefore be a novel therapeutic target for prevention of RV-induced exacerbations.
Plant Cell Environ. 2019 Nov;42(11):3015-3026. doi: 10.1111/pce.13610. Epub 2019 Aug 1.
Sterol isomerase HYDRA1 interacts with RNA silencing suppressor P1b and restricts potyviral infection
Jon Ochoa 1, Adrián Valli 1, Mar Martín-Trillo 1, Carmen Simón-Mateo 1, Juan Antonio García 1, Bernardo Rodamilans 1
Plants use RNA silencing as a strong defensive barrier against virus challenges, and viruses counteract this defence by using RNA silencing suppressors (RSSs). With the objective of identifying host factors helping either the plant or the virus in this interaction, we have performed a yeast two-hybrid screen using P1b, the RSS protein of the ipomovirus Cucumber vein yellowing virus (CVYV, family Potyviridae), as a bait. The C-8 sterol isomerase HYDRA1 (HYD1), an enzyme involved in isoprenoid biosynthesis and cell membrane biology, and required for RNA silencing, was isolated in this screen. The interaction between CVYV P1b and HYD1 was confirmed in planta by Bimolecular Fluorescence Complementation assays. We demonstrated that HYD1 negatively impacts the accumulation of CVYV P1b in an agroinfiltration assay. Moreover, expression of HYD1 inhibited the infection of the potyvirus Plum pox virus, especially when antiviral RNA silencing was boosted by high temperature or by coexpression of homologous sequences. Our results reinforce previous evidence highlighting the relevance of particular composition and structure of cellular membranes for RNA silencing and viral infection. We report a new interaction of an RSS protein from the Potyviridae family with a member of the isoprenoid biosynthetic pathway.
J Virol. 2002 Oct; 76(20): 10465–10472.
A Prenylation Inhibitor Prevents Production of Infectious Hepatitis Delta Virus Particles
Bruno B. Bordier,1,2 Patricia L. Marion,1 Kazuo Ohashi,3 Mark A. Kay,3 Harry B. Greenberg,1,2,4,† John L. Casey,5 and Jeffrey S. Glenn1,2,*
Hepatitis delta virus (HDV) causes both acute and chronic liver disease throughout the world. Effective medical therapy is lacking. Previous work has shown that the assembly of HDV virus-like particles (VLPs) could be abolished by BZA-5B, a compound with farnesyltransferase inhibitory activity. Here we show that FTI-277, another farnesyltransferase inhibitor, prevented the production of complete, infectious HDV virions of two different genotypes. Thus, in spite of the added complexity and assembly determinants of infectious HDV virions compared to VLPs, the former are also sensitive to pharmacological prenylation inhibition. Moreover, production of HDV genotype III virions, which is associated with particularly severe clinical disease, was as sensitive to prenylation inhibition as was that of HDV genotype I virions. Farnesyltransferase inhibitors thus represent an attractive potential class of novel antiviral agents for use against HDV, including the genotypes associated with most severe disease.
Cell Res. 2020 Aug 18 : 1–3.
25-Hydroxycholesterol is a potent SARS-CoV-2 inhibitor
Shulong Zu,#1,2,3 Yong-Qiang Deng,#3 Chao Zhou,#3 Jie Li,#4 Lili Li,1,2 Qi Chen,3 Xiao-Feng Li,3 Hui Zhao,3 Sarah Gold,5 Jun He,6 Xiang Li,7 Changqing Zhang,8 Heng Yang,corresponding author1,2 Genhong Cheng,corresponding author5 and Cheng-Feng Qincorresponding author3
As of July, 2020, the ongoing pandemic of coronavirus diseases 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously 2019-nCoV) has caused more than 10.3 million human infections, with more than 506,000 deaths worldwide according to the World Health Organization. The clinical manifestations of COVID-19 vary from no asymptomatic infection, mild “flu-like” symptoms, to lethal acute respiratory distress syndrome. The case mortality and fatality rates in people infected with SARS-CoV-2 increase steeply with age, and fatal outcomes are almost exclusively seen in people older than 50 years.1 Although the Food and Drug Administration has authorized emergency use of remdesivir for COVID-19 treatment in the US, the need for safe and effective antiviral drugs against SARS-CoV-2 remains urgent and unmet.
25-hydroxycholesterol (25HC) is the product of cholesterol oxidation by the enzyme cholesterol-25-hydroxylase, encoded by the gene CH25H.2 In the innate immune system, CH25H expression is induced in macrophages and dendritic cells in response to various toll-like receptor ligands and interferon (IFN).3 25HC, the enzymatic product of CH25H, is natural oxysterol and can control sterol biosynthesis by regulating sterol-responsive element binding proteins (SREBPs).4,5 Recently, the metabolomic and lipidomic alterations in COVD-19 patients sera have been reported, and 7-hydroxycholesterol, the analogue of 25HC, was up-regulated in COVID-19 patients’ sera.6 Additionally, Wu et al. found the metabolomic and lipidomic were changed in COVID-19 patients’ sera and proposed the plasma biomarkers associated with COVID-19 would be potential therapeutic targets.7 However, whether 25HC is involved in COVID-19 pathogenesis and plays antiviral roles remain not determined.
REVIEW Free Access. First published: 13 January 2021 https://doi.org/10.1002/rmv.2214
Lipid‐based therapies against SARS‐CoV‐2 infection
Eman Humaid Alketbi Rania Hamdy Abdalla El‐Kabalawy Viktorija Juric Marc Pignitter Kareem A. Mosa Ahmed M. Almehdi Ali A. El‐Keblawy Sameh S. M. Soliman
Viruses have evolved to manipulate host lipid metabolism to benefit their replication cycle. Enveloped viruses, including coronaviruses, use host lipids in various stages of the viral life cycle, particularly in the formation of replication compartments and envelopes. Host lipids are utilised by the virus in receptor binding, viral fusion and entry, as well as viral replication. Association of dyslipidaemia with the pathological development of Covid‐19 raises the possibility that exploitation of host lipid metabolism might have therapeutic benefit against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). In this review, promising host lipid targets are discussed along with potential inhibitors. In addition, specific host lipids are involved in the inflammatory responses due to viral infection, so lipid supplementation represents another potential strategy to counteract the severity of viral infection. Furthermore, switching the lipid metabolism through a ketogenic diet is another potential way of limiting the effects of viral infection. Taken together, restricting the access of host lipids to the virus, either by using lipid inhibitors or supplementation with exogenous lipids, might significantly limit SARS‐CoV‐2 infection and/or severity.
Oxf Open Immunol. 2020;1(1):iqaa001. doi: 10.1093/oxfimm/iqaa001. Epub 2020 Jun 18.
Cholesterol-modifying drugs in COVID-19
Nathalie M Schmidt 1, Peter A C Wing 2, Jane A McKeating 2, Mala K Maini 1
Infection with severe acute respiratory syndrom coronavirus 2 (SARS-CoV-2) is more likely to lead to poor outcomes in the elderly and those with cardiovascular disease, obesity or metabolic syndrome. Here, we consider mechanisms by which dyslipidaemia and the use of cholesterol-modifying drugs could influence the virus-host relationship. Cholesterol is essential for the assembly, replication and infectivity of enveloped virus particles; we highlight several cholesterol-modifying drugs with the potential to alter the SARS-CoV-2 life cycle that could be tested in in vitro and in vivo models. Although cholesterol is an essential component of immune cell membranes, excess levels can dysregulate protective immunity and promote exaggerated pulmonary and systemic inflammatory responses. Statins block the production of multiple sterols, oxysterols and isoprenoids, resulting in a pleiotropic range of context-dependent effects on virus infectivity, immunity and inflammation. We highlight antiviral, immunomodulatory and anti-inflammatory effects of cholesterol-modifying drugs that merit further consideration in the management of SARS-CoV-2 infection.
Front Mol Biosci. 2020 Oct 8;7:578964. doi: 10.3389/fmolb.2020.578964. eCollection 2020.
ssRNA Virus and Host Lipid Rearrangements: Is There a Role for Lipid Droplets in SARS-CoV-2 Infection?
Francesca Pagliari 1, Maria Grazia Marafioti 1, Geraldine Genard 1, Patrizio Candeloro 2, Giuseppe Viglietto 3, Joao Seco 1 4, Luca Tirinato 1 2
Since its appearance, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has immediately alarmed the World Health Organization for its very high contagiousness and the complexity of patient clinical profiles. The worldwide scientific community is today gathered in a massive effort in order to develop safe vaccines and effective therapies in the shortest possible time. Every day, new pieces of SARS-CoV-2 infective puzzle are disclosed. Based on knowledge gained with other related coronaviruses and, more in general, on single-strand RNA viruses, we highlight underexplored molecular routes in which lipids and lipid droplets (LDs) might serve essential functions in viral infections. In fact, both lipid homeostasis and the pathways connected to lipids seem to be fundamental in all phases of the coronavirus infection. This review aims at describing potential roles for lipid and LDs in host-virus interactions and suggesting LDs as new and central cellular organelles to be investigated as potential targets against SARS-CoV-2 infection.
Antiviral Res. 2015 Jul;119:1-7. doi: 10.1016/j.antiviral.2015.04.005. Epub 2015 Apr 13.
Modulation of sterol biosynthesis regulates viral replication and cytokine production in influenza A virus infected human alveolar epithelial cells
Kenrie P Y Hui 1, Denise I T Kuok 1, Sara S R Kang 1, Hung-Sing Li 1, Mandy M T Ng 1, Christine H T Bui 1, J S Malik Peiris 1, Renee W Y Chan 1, Michael C W Chan 2
Highly pathogenic H5N1 viruses continue to transmit zoonotically, with mortality higher than 60%, and pose a pandemic threat. Antivirals remain the primary choice for treating H5N1 diseases and have their limitations. Encouraging findings highlight the beneficial effects of combined treatment of host targeting agents with immune-modulatory activities. This study evaluated the undefined roles of sterol metabolic pathway in viral replication and cytokine induction by H5N1 virus in human alveolar epithelial cells. The suppression of the sterol biosynthesis by Simvastatin in human alveolar epithelial cells led to reduction of virus replication and cytokine production by H5N1 virus. We further dissected the antiviral role of different regulators of the sterol metabolism, we showed that Zometa, FPT inhibitor III, but not GGTI-2133 had anti-viral activities against both H5N1 and H1N1 viruses. More importantly, FPT inhibitor III treatment significantly suppressed cytokine production by H5N1 virus infected alveolar epithelial cells. Since both viral replication itself and the effects of viral hyper-induction of cytokines contribute to the immunopathology of severe H5N1 disease, our findings highlights the therapeutic potential of FPT inhibitor III for severe human H5N1 diseases. Furthermore, our study is the first to dissect the roles of different steps in the sterol metabolic pathway in H5N1 virus replication and cytokine production.
Antimicrob Agents Chemother. 2001 Apr; 45(4): 1231–1237.
Antiviral Activity of Lovastatin against Respiratory Syncytial Virus In Vivo and In Vitro
Tara L. Gower1 and Barney S. Graham1,2,*
Respiratory syncytial virus (RSV) is an important human pathogen that can cause severe and life-threatening respiratory infections in infants and immunocompromised adults. We have recently shown that the RSV F glycoprotein, which mediates viral fusion, binds to RhoA. One of the steps in RhoA activation involves isoprenylation at the carboxy terminus of the protein by geranylgeranyltransferase. This modification allows RhoA to be attached to phosphatidyl serine on the inner leaflet of the plasma membrane. Treatment of mice with lovastatin, a drug that inhibits prenylation pathways in the cell by directly inhibiting hydroxymethylglutaryl coenzyme A reductase, diminishes RSV but not vaccinia virus replication when administered up to 24 h after RSV infection and decreases virus-induced weight loss and illness in mice. The inhibition of replication is not likely due to the inhibition of cholesterol biosynthesis, since gemfibrozil, another cholesterol-lowering agent, did not affect virus replication and serum cholesterol levels were not significantly lowered by lovastatin within the time frame of the experiment. Lovastatin also reduces cell-to-cell fusion in cell culture and eliminates RSV replication in HEp-2 cells. These data indicate that lovastatin, more specific isoprenylation inhibitors, or other pharmacological approaches for preventing RhoA membrane localization should be considered for evaluation as a preventive antiviral therapy for selected groups of patients at high risk for severe RSV disease, such as the institutionalized elderly and bone marrow or lung transplant recipients.
Arch Med Sci. 2020; 16(3): 490–496.
Statins and the COVID-19 main protease: in silico evidence on direct interaction
Željko Reiner,1 Mahdi Hatamipour,2,3 Maciej Banach,corresponding author4,5 Matteo Pirro,6 Khalid Al-Rasadi,7 Tannaz Jamialahmadi,8,9 Dina Radenkovic,10 Fabrizio Montecucco,11,12 and Amirhossein Sahebkarcorresponding author13,14,15
No proven drug and no immunisation are yet available for COVID-19 disease. The SARS-CoV-2 main protease (Mpro), a key coronavirus enzyme, which is a potential drug target, has been successfully crystallised. There is evidence suggesting that statins exert anti-viral activity and may block the infectivity of enveloped viruses. The aim of this study was to assess whether statins are potential COVID-19 Mpro inhibitors, using a molecular docking study.
Material and methods
Molecular docking was performed using AutoDock/Vina, a computational docking program. SARS-CoV-2 Mpro was docked with all statins, while antiviral and antiretroviral drugs – favipiravir, nelfinavir, and lopinavir – were used as standards for comparison.
The binding energies obtained from the docking of 6LU7 with native ligand favipiravir, nelfinavir, lopinavir, simvastatin, rosuvastatin, pravastatin, pitavastatin, lovastatin, fluvastatin, and atorvastatin were –6.8, –5.8, –7.9, –7.9, –7.0, –7.7, –6.6, –8.2, –7.4, –7.7, and –6.8 kcal/mol, respectively. The number of hydrogen bonds between statins and amino acid residues of Mpro were 7, 4, and 3 for rosuvastatin, pravastatin, and atorvastatin, respectively, while other statins had two hydrogen bonds.
These results indicate, based upon the binding energy of pitavastatin, rosuvastatin, lovastatin, and fluvastatin, that statins could be efficient SARS-CoV-2 Mpro inhibitors. This is supported by the fact that the effects of some statins, especially pitavastatin, have a binding energy that is even greater than that of protease or polymerase inhibitors. However, further research is necessary to investigate their potential use as drugs for COVID-19.
medRxiv. doi: https://doi.org/10.1101/2020.07.13.20152272. This article is a preprint.
Effect of statins on SARS-CoV-2 infection
Rebecca Moeller, Francisco J. Zapatero-Belinchon, Lisa Lasswitz, Jared Kirui, Graham Brogden, Antonia P. Gunesch, Thomas Pietschmann, Dominic Wichmann, Stefan Kluge, View ORCID ProfileGisa Gerold
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The retrospective analysis of clinical data of patients suffering from COVID-19 has indicated that statin therapy, used to lower plasma cholesterol levels, is associated with a better clinical outcome. We therefore investigated the effect of statins on SARS-CoV-2 infection and found that selective statins reduced SARS-CoV-2 cell entry and inhibited high and low pathogenic coronavirus infection in human cells. A retrospective study on hospitalized patients with COVID-19 implies that reduced high density lipoprotein levels, which are typically counteracted by statin therapy, are associated with aggravated disease outcome. These results suggest that statin therapy poses no additional risk to individuals exposed to SARS-CoV-2 and that some statins may have a mild beneficial effect on COVID-19 outcome. Placebo controlled trials are required to clarify the role of statins in COVID-19 infected patients.