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1.
Biochem J ; 478(23): 4071-4092, 2021 12 10.
Article in English | MEDLINE | ID: covidwho-1556088

ABSTRACT

The COVID-19 pandemic reminds us that in spite of the scientific progress in the past century, there is a lack of general antiviral strategies. In analogy to broad-spectrum antibiotics as antibacterial agents, developing broad spectrum antiviral agents would buy us time for the development of vaccines and treatments for future viral infections. In addition to targeting viral factors, a possible strategy is to understand host immune defense mechanisms and develop methods to boost the antiviral immune response. Here we summarize the role of NAD+-consuming enzymes in the immune defense against viral infections, with the hope that a better understanding of this process could help to develop better antiviral therapeutics targeting these enzymes. These NAD+-consuming enzymes include PARPs, sirtuins, CD38, and SARM1. Among these, the antiviral function of PARPs is particularly important and will be a focus of this review. Interestingly, NAD+ biosynthetic enzymes are also implicated in immune responses. In addition, many viruses, including SARS-CoV-2 contain a macrodomain-containing protein (NSP3 in SARS-CoV-2), which serves to counteract the antiviral function of host PARPs. Therefore, NAD+ and NAD+-consuming enzymes play crucial roles in immune responses against viral infections and detailed mechanistic understandings in the future will likely facilitate the development of general antiviral strategies.


Subject(s)
Antiviral Agents/therapeutic use , Immunity, Innate , NAD/metabolism , Virus Diseases/drug therapy , ADP-ribosyl Cyclase 1/metabolism , Armadillo Domain Proteins/metabolism , COVID-19/drug therapy , COVID-19/immunology , Cytoskeletal Proteins/metabolism , Humans , NAD/immunology , Poly (ADP-Ribose) Polymerase-1/metabolism , Protein Domains , SARS-CoV-2 , Sirtuins/metabolism , Viral Nonstructural Proteins/metabolism , Virus Diseases/immunology
2.
Int J Mol Sci ; 22(16)2021 Aug 12.
Article in English | MEDLINE | ID: covidwho-1354986

ABSTRACT

Human ACE2 and the serine protease TMPRSS2 of novel SARS-CoV-2 are primary entry receptors in host cells. Expression of these genes at the transcriptional level has not been much discussed in detail. The ISRE elements of the ACE2 promoter are a binding site for the ISGF3 complex of the JAK/STAT signaling pathway. TMPRSS2, including IFNß, STAT1, and STAT2, has the PARP1 binding site near to TSS either up or downstream promoter region. It is well documented that PARP1 regulates gene expression at the transcription level. Therefore, to curb virus infection, both promoting type I IFN signaling to boost innate immunity and prevention of virus entry by inhibiting PARP1, ACE2 or TMPRSS2 are safe options. Most importantly, our aim is to attract the attention of the global scientific community towards the codon 72 Single Nucleotide Polymorphism (SNP) of p53 and its underneath role in the innate immune response against SARS-CoV-2. Here, we discuss codon 72 SNP of human p53's role in the different innate immune response to restrict virus-mediated mortality rate only in specific parts of the world. In addition, we discuss potential targets and emerging therapies using bioengineered bacteriophage, anti-sense, or CRISPR strategies.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , COVID-19/immunology , SARS-CoV-2/genetics , Serine Endopeptidases/genetics , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/immunology , Binding Sites , COVID-19/virology , Humans , Immunity, Innate , Poly (ADP-Ribose) Polymerase-1/chemistry , Poly (ADP-Ribose) Polymerase-1/genetics , Poly (ADP-Ribose) Polymerase-1/immunology , Poly (ADP-Ribose) Polymerase-1/metabolism , Polymorphism, Single Nucleotide , SARS-CoV-2/physiology , Serine Endopeptidases/chemistry , Serine Endopeptidases/immunology , Vaccination , Virus Internalization
3.
Int J Mol Sci ; 22(11)2021 May 21.
Article in English | MEDLINE | ID: covidwho-1244038

ABSTRACT

In late 2019, a new member of the Coronaviridae family, officially designated as "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), emerged and spread rapidly. The Coronavirus Disease-19 (COVID-19) outbreak was accompanied by a high rate of morbidity and mortality worldwide and was declared a pandemic by the World Health Organization in March 2020. Within the Coronaviridae family, SARS-CoV-2 is considered to be the third most highly pathogenic virus that infects humans, following the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). Four major mechanisms are thought to be involved in COVID-19 pathogenesis, including the activation of the renin-angiotensin system (RAS) signaling pathway, oxidative stress and cell death, cytokine storm, and endothelial dysfunction. Following virus entry and RAS activation, acute respiratory distress syndrome develops with an oxidative/nitrosative burst. The DNA damage induced by oxidative stress activates poly ADP-ribose polymerase-1 (PARP-1), viral macrodomain of non-structural protein 3, poly (ADP-ribose) glycohydrolase (PARG), and transient receptor potential melastatin type 2 (TRPM2) channel in a sequential manner which results in cell apoptosis or necrosis. In this review, blockers of angiotensin II receptor and/or PARP, PARG, and TRPM2, including vitamin D3, trehalose, tannins, flufenamic and mefenamic acid, and losartan, have been investigated for inhibiting RAS activation and quenching oxidative burst. Moreover, the application of organic and inorganic nanoparticles, including liposomes, dendrimers, quantum dots, and iron oxides, as therapeutic agents for SARS-CoV-2 were fully reviewed. In the present review, the clinical manifestations of COVID-19 are explained by focusing on molecular mechanisms. Potential therapeutic targets, including the RAS signaling pathway, PARP, PARG, and TRPM2, are also discussed in depth.


Subject(s)
COVID-19/drug therapy , COVID-19/therapy , Cytokine Release Syndrome/drug therapy , Nanomedicine/methods , Oxidative Stress/drug effects , Poly (ADP-Ribose) Polymerase-1/metabolism , SARS-CoV-2/drug effects , Apoptosis/drug effects , COVID-19/metabolism , COVID-19/physiopathology , Cholecalciferol/pharmacology , GTPase-Activating Proteins/antagonists & inhibitors , GTPase-Activating Proteins/metabolism , Humans , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Renin-Angiotensin System/drug effects , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , TRPM Cation Channels/antagonists & inhibitors , TRPM Cation Channels/metabolism , Tannins/pharmacology , Trehalose/pharmacology
4.
Biosci Rep ; 40(10)2020 10 30.
Article in English | MEDLINE | ID: covidwho-989979

ABSTRACT

COVID-19 induces a proinflammatory environment that is stronger in patients requiring intensive care. The cytokine components of this environment may determine efficacy or otherwise of glucocorticoid therapy. The immunity modulators, the aryl hydrocarbon receptor (AhR) and the nuclear NAD+-consuming enzyme poly (ADP-ribose) polymerase 1 (PARP 1) may play a critical role in COVID-19 pathophysiology. The AhR is overexpressed in coronaviruses, including COVID-19 and, as it regulates PARP gene expression, the latter is likely to be activated in COVID-19. PARP 1 activation leads to cell death mainly by depletion of NAD+ and adenosine triphosphate (ATP), especially when availability of these energy mediators is compromised. PARP expression is enhanced in other lung conditions: the pneumovirus respiratory syncytial virus (RSV) and chronic obstructive pulmonary disease (COPD). I propose that PARP 1 activation is the terminal point in a sequence of events culminating in patient mortality and should be the focus of COVID-19 immunotherapy. Potent PARP 1 inhibitors are undergoing trials in cancer, but a readily available inhibitor, nicotinamide (NAM), which possesses a highly desirable biochemical and activity profile, merits exploration. It conserves NAD+ and prevents ATP depletion by PARP 1 and Sirtuin 1 (silent mating type information regulation 2 homologue 1) inhibition, enhances NAD+ synthesis, and hence that of NADP+ which is a stronger PARP inhibitor, reverses lung injury caused by ischaemia/reperfusion, inhibits proinflammatory cytokines and is effective against HIV infection. These properties qualify NAM for therapeutic use initially in conjunction with standard clinical care or combined with other agents, and subsequently as an adjunct to stronger PARP 1 inhibitors or other drugs.


Subject(s)
Coronavirus Infections/drug therapy , Niacinamide/pharmacology , Pneumonia, Viral/drug therapy , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Basic Helix-Loop-Helix Transcription Factors/metabolism , Betacoronavirus/drug effects , COVID-19 , Cell Line , Coronavirus Infections/pathology , Cytokines/blood , Humans , Immunotherapy/methods , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Kynurenine/metabolism , Pandemics , Pneumonia, Viral/pathology , Poly (ADP-Ribose) Polymerase-1/metabolism , Receptors, Aryl Hydrocarbon/metabolism , SARS-CoV-2
5.
Am J Respir Cell Mol Biol ; 63(5): 571-590, 2020 11.
Article in English | MEDLINE | ID: covidwho-901528

ABSTRACT

PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)-associated ALI.


Subject(s)
Acute Lung Injury/drug therapy , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Lung/drug effects , Pneumonia, Viral/drug therapy , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Acute Lung Injury/enzymology , Acute Lung Injury/virology , Animals , Antiviral Agents/adverse effects , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Lung/enzymology , Lung/virology , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , SARS-CoV-2 , Signal Transduction/drug effects
6.
Nucleic Acids Res ; 48(17): 9694-9709, 2020 09 25.
Article in English | MEDLINE | ID: covidwho-745778

ABSTRACT

DNA breaks recruit and activate PARP1/2, which deposit poly-ADP-ribose (PAR) to recruit XRCC1-Ligase3 and other repair factors to promote DNA repair. Clinical PARP inhibitors (PARPi) extend the lifetime of damage-induced PARP1/2 foci, referred to as 'trapping'. To understand the molecular nature of 'trapping' in cells, we employed quantitative live-cell imaging and fluorescence recovery after photo-bleaching. Unexpectedly, we found that PARP1 exchanges rapidly at DNA damage sites even in the presence of clinical PARPi, suggesting the persistent foci are not caused by physical stalling. Loss of Xrcc1, a major downstream effector of PAR, also caused persistent PARP1 foci without affecting PARP1 exchange. Thus, we propose that the persistent PARP1 foci are formed by different PARP1 molecules that are continuously recruited to and exchanging at DNA lesions due to attenuated XRCC1-LIG3 recruitment and delayed DNA repair. Moreover, mutation analyses of the NAD+ interacting residues of PARP1 showed that PARP1 can be physically trapped at DNA damage sites, and identified H862 as a potential regulator for PARP1 exchange. PARP1-H862D, but not PARylation-deficient PARP1-E988K, formed stable PARP1 foci upon activation. Together, these findings uncovered the nature of persistent PARP1 foci and identified NAD+ interacting residues involved in the PARP1 exchange.


Subject(s)
DNA Damage , DNA Repair/drug effects , Poly (ADP-Ribose) Polymerase-1/genetics , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Binding Sites , Catalytic Domain , Cell Line, Tumor , DNA Repair/physiology , Fluorescence Resonance Energy Transfer , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Humans , Indazoles/pharmacology , Kinetics , Molecular Imaging , NAD/metabolism , Piperidines/pharmacology , Poly(ADP-ribose) Polymerases/genetics , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , X-ray Repair Cross Complementing Protein 1/genetics , X-ray Repair Cross Complementing Protein 1/metabolism
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