key: cord-0897509-rbxymftg
authors: Curtin, Nicola; Bányai, Krisztián; Thaventhiran, James; Le Quesne, John; Helyes, Zsuzsanna; Bai, Péter
title: Repositioning PARP inhibitors for SARS‐CoV‐2 infection (COVID‐19); a new multi‐pronged therapy for ARDS?
date: 2020-05-22
journal: Br J Pharmacol
DOI: 10.1111/bph.15137
sha: c7ad394d621ba607b0c0ed4374bf32db9ebc69bc
doc_id: 897509
cord_uid: rbxymftg

Clinically approved PARP inhibitors (PARPi) have a mild adverse effect profile and are well‐tolerated as continuous daily oral therapy. We review the evidence that justifies the repurposing of PARPi to block the proliferation of SARS‐CoV‐2 and combat the life‐threatening sequelae of COVID‐19 by several mechanisms. PARPi’s can effectively decrease IL‐6, IL‐1 and TNFα levels (key interleukins in SARS‐CoV‐2‐induced cytokine storm) and can alleviate subsequent lung fibrosis, as demonstrated in murine experiments and clinical trials. PARPi can tune macrophages towards a tolerogenic phenotype. PARPi’s may also counteract SARS‐CoV‐2‐induced and inflammation‐induced cell death and support cell survival. PARPi’s had beneficial effects in animal models of acute respiratory distress syndrome (ARDS), asthma and ventilator‐induced lung injury. PARPi’s may potentiate the effectiveness of Tocilizumab, Anakinra, Sarilumab, Adalimumab, Canakinumab or Siltuximab therapy. In summary, the evidence suggests that PARPi therapy would benefit COVID‐19 patients and trials of these drugs should be undertaken.

The newly emerging coronavirus disease, COVID-19 (Coronavirus Disease 2019) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . The SARS-CoV-2 belongs to the Coronaviridae family, being genetically related to the human pathogen SARS-CoV-1 and MERS-CoV and to a number of bat-origin coronaviruses (CoVs) . SARS-CoV-2 is an enveloped virus that has a positive sense singlestranded RNA (ssRNA+) genome of nearly 30,000 nucleotide in length .

The first site of viral infection is the upper respiratory tract. At a later stage of infection the virus may disseminate to and replicate in the lower respiratory tract . Viral RNA and infectious virus can be found in the nasopharyngeal swab and the sputum. In addition, infection of the gastrointestinal tract has been reported and infectious viruses can be isolated from fecal specimens . The virus uses the Angiotensin-converting enzyme 2 (ACE2) as cellular receptor and a type II transmembrane serine protease, TMPRSS2, as co-factor that activates the attachment protein of SARS-CoV-2 to aid viral entry into epithelial cells of the respiratory and in the gastrointestinal tract . In the majority of the cases, patients have very mild symptoms. However, a considerable portion of the patients develop severe symptoms and require intensive care and mechanical ventilation; this patient group shows an increased risk for death Guan et al., 2020; Huang et al., 2020) . The risk factors for complications and mortality include pre-existing cardiovascular, metabolic or neoplastic diseases and older age (Nikolich-Zugich et al., 2020; Zhou et al., 2020) . Men have higher chance for developing severe symptoms, as well as, for fatal outcome Huang et al., 2020) .

Although the pathogenesis of COVID-19 is not fully understood, immunopathological mechanisms are thought to play an important role. A detrimental sequel of SARS-CoV-2 virus infection is cytokine storm (also called cytokine release syndrome or macrophage overactivation syndrome) that occurs after the elimination of the virus and culminates in multiple organ failure (Mehta et al., 2020; Shi et al., 2020) . Cytokine storm may be responsible for a considerable fraction of adverse outcomes in SARS-CoV-2 infection .

The reason for the absence of the adaptive response is unknown. In clinical practice Tocilizumab, an antibody against IL-6 ( Luo et al., 2020; McGonagle et al., 2020; Toniati et al., 2020) and Anakinra, an IL-1 receptor antagonist (Adam Monteagudo et al., 2020; McGonagle et al., 2020) were used successfully to cope with SARS-Cov-2-induced cytokine storm suggesting the involvement of these interleukins. Other drugs, primarily used in a rheumatologic settings, are also suggested to be used to block cytokine storm (Ceribelli et al., 2020) .

The current treatment options in SARS-CoV-2 infection are limited to drugs empirically tested in the clinical setting. The unmet medical need posed by SARS-CoV-2 infection calls for rapid repositioning of available drugs. These drugs are mostly antiviral drugs (e.g.

Lopinavir-Ritonavir combinational therapy, Remedsivir) or anti-inflammatory drugs, as noted above. None of the current COVID-19 treatments are supported by prospective randomized clinical trials and, therefore, all of these treatments should be considered with caution. The World Health Organization initiated a large scale drug repositioning study to rapidly assess the most promising candidates to fight SARS-CoV-2 pandemic. In this position paper we are reviewing the applicability of PARP inhibitors and their possible interactions with known therapeutic options in SARS-CoV-2 infection.

Poly(ADP-ribose) polymerase (PARPs/ARTDs) enzymes constitute a family of 17 members in humans (PARP1-PARP17) (Ame et al., 2004) . When activated, PARPs cleave their substrate, NAD+, and couple the resulting ADP-ribose units onto acceptor proteins forming mono, oligo or polymers of ADP-ribose. The polymer of ADP-ribose is called poly(ADP-ribose) (PAR). The large, negatively charged mono, oligo or polymers heavily impact on the behavior of target proteins and a huge number of proteins were shown to be ADP-ribosylated or PARylated on multiple different amino acids (Bai, 2015) . In addition, ADPribose units can serve as binding surface for proteins (Tartier et al., 2003) .

Macrodomain-containing proteins constitute a small protein family (Karlberg et al., 2013) .

Macrodomains can bind to ADP-ribose units and some can hydrolyze ADP-ribose units upon binding (Karlberg et al., 2013) . Through binding or hydrolyzing ADP-ribose, macrodomaincontaining proteins can translate ADP-ribosylation signals into cellular adaptation programs.

Macrodomains can be found in all domains of life, including viruses and more specifically, coronaviruses (Grunewald et al., 2019) . PARP1 is responsible for ~85-90% of cellular PARP activity, PARP2 is responsible for 10-15%, while the rest of the enzymes share the remainder of all cellular PARP activity (Schreiber et al., 2002) . Active PARPs represent a large burden on cellular NAD+ levels (Sims et al., 1983) . Although, originally excess PARP activation is linked to DNA damage-associated pathologies, recent advances showed that PARP activity under physiological conditions also represents a large burden on cellular NAD+ levels (Bai et al., 2011a; Bai et al., 2011b; Mohamed et al., 2014) . PARP1, PARP2 and PARP3 can be activated by binding to irregular or damaged DNA (Bai, 2015) that is often the result of reactive oxygen (ROS) or reactive nitrogen species (RNS) This article is protected by copyright. All rights reserved. production under inflammatory conditions (Bai & Virag, 2012) . The activation of PARP1, PARP2 and PARP3 is vital for initiating DNA repair and the resolution of irregular DNA structures and modulating chromatin structure. Through these, certain PARP isoforms (chiefly, PARP1) are involved in recombination and transcription events that encompass changes to DNA structure (Bai, 2015) . Importantly, PARP2 can bind to RNA, which may activate the enzyme (Leger et al., 2014) . There are other pathways to activate PARPs involving signal transduction pathways (Bai, 2015) . PARP enzymes were shown to be involved in transcription, mRNA handling and polypeptide elongation (for comprehensive reviews see (Kim et al., 2020) ).

PARP enzymes are involved in a wide variety of cellular processes, among these, their impact in cell death, immune function (Bai & Virag, 2012; Fehr et al., 2020) , antiviral response Fehr et al., 2020) , transcription, translation (Kim et al., 2020) and autophagy (Rodríguez-Vargas et al., 2019) are relevant for our discussion. PARP inhibitors (PARPi) that are in current clinical use (Olaparib, Rucaparib, Niraparib and Talazoparib) are inhibitors of PARP1, PARP2 and PARP3 (Wahlberg et al., 2012) .

The protective effect of PARPi, that is applicable to non-oncological models of inflammation, was first suggested by Nathan Berger's group nearly 40 years ago (Sims et al., 1983) . They noted that DNA damage-induced cell death was associated with PARP activation, resulting in massive depletion of its substrate, NAD+, and consequently ATP that resulted in necrosis. Depletion of these pools was prevented in the presence of a PARPi and necrosis reduced. Subsequently it has also been shown that the product of the PARP reaction, i.e. PAR can also trigger apoptosis-inducing factor (AIF) release that promotes a specific programmed cell death pathway called "parthanatos" (Fatokun et al., 2014) . Relevant to inflammatory normal tissue damage in general, and ARDS in particular, is the role of oxidative and nitrosative stress, which is integral to inflammation and causes DNA strand breakage that massively activates PARP (Bai & Virag, 2012; Ke et al., 2019) . Indeed PARP can actively increase and prolong inflammation through a vicious cycle of ROS/RNS-induced DNA damage, PARP-mediated necrosis and increase in inflammatory cytokines (Figure 1.) . PARPi have been shown to limit inflammation-induced normal tissue damage, including acute lung injury, in animal models (reviewed in (Pazzaglia & Pioli, 2019; Virág, 2005) ).

Reactive species production increases in SARS-CoV-2 (COVID-19) infection (Kouhpayeh et al., 2020; Sawalha et al., 2020; Wang et al., 2020; Zhang et al., 2020b ) that makes PARP activation and PARP activation-mediated cell death likely. Pharmacological PARP inhibition is This article is protected by copyright. All rights reserved.

likely to reduce cell death under these conditions as suggested by the study on another ssRNA(+) virus, the Zika virus. Zika virus-induced cell death was effectively blocked by PARP inhibition . The source of the reactive species can be diverse, stemming from activated immune (e.g. macrophages) or dysfunctional cells. Interestingly, the nucleocapsid protein of SARS-CoV-1 can induce reactive oxygen species production in non-immune cells too that can be a pathway in the case of SARS-Cov-2 as well (Zhang et al., 2007) . In fact, a prepublication paper (Heer et al., 2020) already suggested that SARS-CoV-2 infection induces PARP activity.

PARP1 is the best characterized member of the PARP family from the perspective of immune processes. PARP1 seems to have mostly pro-inflammatory properties in terms of Th1 and Th2-mediated processes (Bai & Virag, 2012; Fehr et al., 2020) . PARP2 has limited role in pro-inflammatory processes (Bai & Virag, 2012) . Pharmacological PARP inhibition is generally anti-inflammatory. PARP1 is involved in regulating innate and adaptive immunity through mediating signal transduction and transcription events in multiple immune cell lines that is translated to differential expression of cytokines and chemokines, as well as, their receptors (Bai & Virag, 2012; Fehr et al., 2020) .

In humans there is evidence that the polymorphism in PARP1 (V762A) that confers reduced activity, is associated with reduced risk of asthma (Ozaydin et al., 2014) . PARP activity is increased in the lung tissues of asthmatic patients and in mouse models the PARPi, olaparib, prevents asthma indicating that the extrapolations from preclinical models to human conditions are valid (Ghonim et al., 2015b) . Also, PARP inhibition confers protection to the lungs upon acute lung injury inflicted by various noxae (burn, smoke inhalation, bacterial infection, etc.) (Hamahata et al., 2012; Murakami et al., 2004) in a nuclear factor-κB (NFκB)dependent fashion (Ahmad et al., 2015; Wang et al., 2013) . Various PARPi (3-AB, PJ-34 and INO-1001) have been shown to be protective in various preclinical models of acute respiratory distress syndrome (ARDS) by reducing production of inflammatory mediators and preventing depletion of NAD+ and ATP, and also the deterioration of barrier function that may contribute to exudate formation in ARDS (reviewed in (Virág, 2005) ). The most common animal model of human acute lung injury/ARDS is intratracheal instillation of lipopolysaccharide (LPS).

PARP plays an important role in the pathogenesis of LPS-mediated ARDS damage by a variety of mechanisms, and both genetic disruption of PARP1 and inhibition of PARP ameliorates ARDS and ARDS-associated tissue damage (reviewed in (Sethi et al., 2017) ).

Following LPS administration olaparib not only reduced inflammatory cell infiltration in the lung and pulmonary oedema and exudate, but also reduced secondary kidney injury (Kapoor et al., 2015) . Relevance to human lung disease comes from the observation that in cases of chronic obstructive pulmonary disease (COPD), plasma NAD+ is low and both DNA damage, PARP activity and the percentage of PAR positive lymphocytes were higher than in control subjects (Hageman et al., 2003; Oit-Wiscombe et al., 2013) .

PARP inhibition has an additional lung protective feature. PARPi's are able to reduce lung fibrosis, a common sequel of SARS-Cov-2 lung inflammation, in different preclinical animal models (Carlile et al., 2016; Hoyt & Lazo, 1992 , 1993 Lucarini et al., 2017) . PARP activity in idiopathic lung fibrosis patients was higher than in healthy controls (Hu et al., 2013) suggesting that the findings of the animal models can be translated to the human situation.

As we noted above, a major reason of mortality in SARS-CoV-2 (COVID-19) infection is the macrophage overactivation that leads to cytokine storm and, consequently, to multi-organ failure (Vaninov, 2020) . To date, IL-6 and IL-1 were implicated in SARS-CoV-2 (COVID-19)induced cytokine storm (Conti et al., 2020; McGonagle et al., 2020) , however, the involvement of tumor necrosis factor α (TNFα) is also likely.

PARPi's, including olaparib can reduce the expression of IL-6 in multiple organs, including the lung (Ghonim et al., 2015a; Kim et al., 2008; Liaudet et al., 2002; Pagano et al., 2007; Sahu et al., 2020) in animal models. Importantly and in good agreement with the previous dataset, pharmacological PARP inhibition using INO-1001 in humans reduced serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels (Morrow et al., 2009 ) further reinforcing the notion that data from preclinical studies can be translated to humans.

infection is interleukin-1 (IL-1) (Conti et al., 2020; McGonagle et al., 2020) . PARPi's, including olaparib, can decrease IL-1β expression in animal models (Liaudet et al., 2002; Mabley et al., 2001; Sahu et al., 2020; Sethi et al., 2019) that, again, points out the applicability of PARPi's to dampen IL-1 expression in humans. Finally, pharmacological PARP inhibition, including with the clinically approved PARPi, olaparib, reduced TNFα levels in the lungs in various animal models of lung inflammation (Cuzzocrea et al., 2002; Kim et al., 2008; Liaudet et al., 2002; Sahu et al., 2020; Virag et al., 2004) .

The data we presented suggest that PARP inhibition can counteract inflammationinduced cell death, possibly counteracts the ARDS-like features and cytokine storm through blocking macrophage overactivation (cytokine storm) through downregulating the expression of IL-6, IL-1 and TNFα in humans. These events represent a vicious circle that is sustained by PARP1 activation, therefore, PARPi can break the chain of events at multiple loci (as suggested in (Jagtap & Szabo, 2005) ) and exert cytoprotective effects on the pulmonary epithelial and endothelial cells.

SARS-Cov-2-infected patients requiring intensive care often need mechanical ventilation over extended periods . Pharmacological inhibition of PARP reduced the This article is protected by copyright. All rights reserved.

inflammatory component of ventilation-induced lung damage in a murine model (Kim et al., 2008) . Furthermore, in another rat preclinical model of severe acute lung injury the PARPi PJ-34 protected the kidney from injury following mechanical ventilation (Vaschetto et al., 2010) . Similar findings were obtained in an ovine model where acute lung injury was induced by smoke inhalation and local Pseudomonas aeruginosa colonization (Murakami et al., 2004 ). It appears that in ventilation-induced lung damage (VILI) PARP inhibition breaks a similar vicious cycle as in ARDS or other inflammatory models (Jagtap & Szabo, 2005) . The similarity of the findings in rodent and large animal models supports the potential for translating these findings to the human situation.

Several members of the PARP family are involved in host-virus interactions, and by our current understanding, most PARP enzymes have antiviral properties Grunewald et al., 2020) . PARPs impact on multiple steps of the viral life cycle, these steps are mostly related to the nucleic acid-binding properties of PARPs. PARPs can interfere with viral integration, recombination and transcription , however, these are not relevant in the context of coronaviruses.

have protective function . Interferon treatment induces a set of PARP enzymes PARP9, PARP10, PARP12 and PARP14 in cells (Grunewald et al., 2019) . These PARP enzymes inhibit viral translation probably through ADP-ribosylating key cellular proteins (Grunewald et al., 2019) .

Hepeviridae encode macrodomain proteins that bind to and hydrolyze ADP-ribose from proteins and are critical for optimal replication and virulence (Grunewald et al., 2019; Grunewald et al., 2020) . The conserved coronavirus macrodomain in SARS-CoV was found to play a role in viral replication and to suppress IFN and cytokine production (Grunewald et al., 2019; Grunewald et al., 2020) .

Interestingly, the nucleocapsid protein of SARS-CoV and a number of other CoV's are ADPribosylated (Grunewald et al., 2018 ), yet, the significance of this posttranslational modification is unexplored.

Since PARP inhibitors have preference towards PARP1, PARP2 and PARP3 (Wahlberg et al., 2012) it is unlikely that PARPi treatment would interfere with the antiviral effects of the minor PARP isoforms. An interesting and potentially relevant findings are that another PARPi, PJ34, can form a complex with the nucleocpasid protein of the human coronavirus CoV-OC43 and, hence, can hinder its RNA binding affinity (Lin et al., 2014) .

The World Health Organization (WHO) initiated a large-scale drug repurposing clinical trial entitled Solidarity (WHO, 2020). In the frame of this trial four treatment schemes will be assessed, 1) Remedsivir, 2) Lopinavir-Ritonavir combination, 3)

chloroquine/hydrochloroquine and 4) interferon beta. Empirical clinical data suggest the applicability of biological therapy drugs to combat cytokine storm. Here, we will evaluate the potential for PARPi in combination with the drugs investigated in the Solidarity trial.

Combination therapy is particularly advantageous, since it requires lower doses with better tolerability of the components. As we noted earlier, none of the current COVID-19 treatments are supported by prospective randomized clinical trials and, therefore, all of these treatments should be considered with caution.

To date, PARPi's have not been reported to interact with Ritonavir, Lopinavir or

Remedsivir. Interferon beta, has pleiotropic antiviral actions, and therefore, probably interferon beta can induce the antiviral function of PARPs.

Chloroquine and hydroxychloroquine are antimalarial and antirheumatic drugs that were assessed in small scale cohorts in France and China Gautret et al., 2020) .

Although criticism was raised concerning the available studies and the potential cardiotoxicity of both drugs, the WHO included chloroquine and hydroxychloroquine to kick-off a multicenter, large population study. Chloroquine and hydroxychloroquine probably block the processing of SARS-CoV-2 by blocking the acidification of the vesicles containing the virus, in a process biochemically similar to the process of autophagy. Of note, the genetic or pharmacological inhibition of PARP1 blocks the early steps of autophagy (Rodríguez-Vargas et al., 2019) . Furthermore, the genetic or pharmacological inhibition of PARP2 blocks the degradation of the cargo of autophagic vesicles mimicking the action of chloroquine (Janko et al., 2020) . From these observations one may extrapolate that PARPi's could potentiate the antiviral effects of chloroquine or hydoxychloroquine, and could be exploited to achieve dose reduction of chloroquine or hydoxychloroquine. It is also of note that ADP-ribosylation-mediated autophagic processes were found to be important in the pathogenesis of other microorganisms such as Legionella in high-profile studies (e.g. (Kalayil et al., 2018) ). Nevertheless, links between PARPi's and chloroquine are purely hypothetical.

IL-6 is a key interleukin in sustaining cytokine storm following SARS-CoV-2 infection (Zhang et al., 2020a) . Studies have shown that anti-IL-6 immunotherapy using Tocilizumab was beneficial for patients McGonagle et al., 2020) . As we noted earlier, PARP inhibition was shown to reduce IL-6 expression in humans, therefore, it is possible that PARP inhibition could also potentiate the effects of anti-IL-6 (Tocilizumab, Siltuximab) or anti-IL-6 receptor (Sarilumab) treatment.

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Preclinical data suggest that PARPi's can reduce IL-1 (Liaudet et al., 2002; Mabley et al., 2001; Sethi et al., 2019) and TNFα expression (Kim et al., 2008; Liaudet et al., 2002; Virag et al., 2004) , it is possible therefore, that PARPi's could potentiate Canakinumab (IL-1β antibody), Anakinra (IL-1 receptor antagonist) and Adalimumab (TNFα antibody) therapy.

Four PARPi are approved by the Food and Drug Administration (FDA) and European

Medicines Agency (EMA) for cancer therapy. Although, the original rationale for their development was to overcome DNA repair-mediated resistance to DNA damaging anticancer therapy, their approval has been as single agents exploiting tumor-specific defects in the complementary DNA repair pathway homologous recombination repair (HRR) by a process known as synthetic lethality.

Currently PARPi are only approved for cancer therapy as single agents (Table 1. ). The first to be approved was olaparib, now called Lynparza®. Originally approved by the FDA at the end of 2014 at a dose of 400 mg twice daily in capsule formulation, it is now approved in tablet formulation at 300 mg twice daily for maintenance (including front-line) therapy in ovarian cancer. It is also approved at the same dose and schedule for metastatic breast and pancreatic cancer in individuals with germline BRCA mutations. Also approved in ovarian cancer are rucaparib (Rubraca®) at 600 mg orally twice daily and niraparib (Zejula®) 300 mg orally once daily. Talazoparib (Talzenna®) is the most potent of all the PARPi and has been approved at dose of only 1 mg daily for germline BRCA mutated metastatic breast cancer.

Veliparib is a less potent PARPi that has so far failed to show sufficient single agent activity for approval but has been in advanced clinical trial alone and in combination with other anticancer agents for over a decade.

Due to their tumor-specific synthetic lethality their toxicity as monotherapies is mild and (Curtin, 2020) .

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It is anticipated that the doses needed for non-oncological diseases e.g. ARDS is likely to be lower (and hence less toxic) for 2 reasons. Firstly, the doses found to be effective preclinically in non-oncological models are 1-2 orders of magnitude lower than the monotherapy doses used in cancer models (reviewed in (Berger et al., 2018) ). This is likely to reflect the intracellular concentrations needed to maintain NAD+ pool from excessive depletion vs. those needed to completely block repair for a sustained period. Secondly, the approved doses are largely based on dose escalation Phase I trials where the end-point is tolerability, which may not be appropriate for a tumor-specific drug and may be well in excess of the effective dose.

The evidence we describe above indicates that PARPi's may have beneficial effects in SARS-CoV-2 infection and its sequelae by preventing macrophage overactivation and the subsequent cytokine storm, as well as, by protecting cells against cell death. It is also of note that PARP inhibitors were protective against risk factors for bad clinical outcomes of SARS-CoV-2 infection, such as cardiovascular and metabolic diseases (Bai, 2015) . Importantly,

PARPi's are cytoprotective in the central nerve system (Fatokun et al., 2014) and the cardiovascular system (Bai, 2015) , the systems that are damaged in COVID-19 patients with bad clinical outcome.

Of particular interest regarding COVID-19 is the sex bias of the mortality statistics. Men are more than twice as likely to die as women Huang et al., 2020) . Previous research has shown that men have on average 40% higher PARP activity than women, at least in their PBMCs, with similar sex differences in mice (Mabley et al., 2005; Zaremba et al., 2011) . In most pre-clinical studies where the protective effects of PARPi were evaluated, only male animals have been used. However, in those studies where both sexes were included, the protective effects of PARPi were less pronounced in females (reviewed in (Berger et al., 2018; Curtin & Szabo, 2013) ). There are no data for sex differences in PARP activity in human lung tissue due to the difficulty of obtaining viable normal lung tissue. However, in humans following traumatic brain injury men were 2.6 times more likely than women to have elevated PAR-modified proteins in their CSF after comparable levels of trauma and, strikingly similar to the studies in PBMCs, the mean PAR level was approximately 40% higher in males than females (Sarnaik et al., 2010) .

Currently there are over 600 registered clinical trials investigating COVID-19, not one of which includes a PARPi. The preclinical evidence suggests that 5-10% of the currently approved PARPi doses would be sufficient/effective and tolerable. Finally, given there has been no FDA approved therapy for ARDS (reviewed in (Standiford & Ward, 2016) ) we believe that the preclinical data and scientific rationale justifies investigations with (low dose?) PARPi.

References to this review were identified through the prior knowledge of the authors that was complemented by systematic search of Pubmed by using the combinations "PARP IL-6", "PARP IL-1", "PARP TNFa/alpha", "PARP virus", "PARP SARS", "virus macrodomain", "PARP fibrosis lung", "PARP remedsivir", "PARP ritonavir", "PARP lopinavir", "PARP chloroquine", "PARP hydroxychloroquie". Articles published in English were included with no restriction on publication date. 

Infection-induced reactive oxygen species (ROS) and reactive nitrogen species (RNS) cause DNA strand breakage. This activates PARP1 and PARP2, which generates poly(ADP-ribose) (PAR) that can lead to apoptosis-inducing factor (AIF) release leading to cell death by parthanatos. This reaction also depletes NAD+ and subsequently ATP leading to necrosis, which causes further inflammation and activation of immune cells (e.g. macrophages) leading to more ROS and RNS generation and, so, a vicious cycle of further PARP activation and downstream consequences. PARP activation also stimulates the production of inflammatory cytokines, such as IL-6, further contributing to this vicious cycle. All of this can essentially be blocked by the use of a PARPi. 

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Murine strain differences in acute lung injury and activation of poly(ADP-ribose) polymerase by in vitro exposure of lung slices to bleomycin

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Regulation of myofibroblast differentiation by poly(ADP-ribose) polymerase 1

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Silencing of PARP2 Blocks Autophagic Degradation

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PARP inhibitor, olaparib ameliorates acute lung and kidney injury upon intratracheal administration of LPS in mice

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PARPs and ADP-ribosylation in RNA biology: from RNA expression and processing to protein translation and proteostasis

Inflammatory and transcriptional roles of poly (ADP-ribose) polymerase in ventilator-induced lung injury

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A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

Exploring and comparing adverse events between PARP inhibitors

Olaparib maintenance therapy in platinumsensitive relapsed ovarian cancer

ARTD2 activity is stimulated by RNA

Activation of poly(ADP-Ribose) polymerase-1 is a central mechanism of lipopolysaccharide-induced acute lung inflammation

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HYDAMTIQ, a selective PARP-1 inhibitor, improves bleomycininduced lung fibrosis by dampening the TGF-beta/SMAD signalling pathway

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Gender differences in the endotoxin-induced inflammatory and vascular responses: potential role of poly(ADP-ribose) polymerase activation

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The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease

COVID-19: consider cytokine storm syndromes and immunosuppression

Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer

MicroRNA-149 inhibits PARP-2 and promotes mitochondrial biogenesis via SIRT-1/PGC-1alpha network in skeletal muscle

Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer

Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial

A randomized, placebo-controlled trial to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamics of a potent inhibitor of poly(ADP-ribose) polymerase (INO-1001) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the TIMI 37 trial

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SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes

Increased DNA damage in progression of COPD: a response by poly(ADP-ribose) polymerase-1

Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2

Investigation of poly (ADP-ribose) polymerase-1 genetic variants as a possible risk for allergic rhinitis

Poly(ADP-ribose) polymerase-1 (PARP-1) controls lung cell proliferation and repair after hyperoxia-induced lung damage

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

Olaparib tablets as maintenance therapy in patients with platinumsensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled

Randomized, Placebo-Controlled, Phase II Study of Veliparib in Combination with Carboplatin and Paclitaxel for Advanced/Metastatic Non-Small Cell Lung Cancer

Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation

PARP1 and Poly(ADPribosyl)ation Signaling during Autophagy in Response to Nutrient Deprivation

Pharmacological inhibition of poly (ADP-ribose) polymerase by olaparib, prevents acute lung injury associated cognitive deficits potentially through suppression of inflammatory response

Influence of PARP-1 polymorphisms in patients after traumatic brain injury

Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients

Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1

Poly(ADP-Ribose)Polymerase-1 in Lung Inflammatory Disorders: A

PARP inhibition by olaparib alleviates chronic asthma-associated remodeling features via modulating inflammasome signaling in mice

COVID-19 infection: the perspectives on immune responses

Poly(ADP-ribose) Polymerase inhibitors preserve nicotinamide adenine dinucleotide and adenosine 5'-triphosphate pools in DNA-damaged cells: mechanism of stimulation of unscheduled DNA synthesis

Therapeutic targeting of acute lung injury and acute respiratory distress syndrome

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

Local DNA damage by proton microbeam irradiation induces poly(ADP-ribose) synthesis in mammalian cells

Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in

In the eye of the COVID-19 cytokine storm

Renal hypoperfusion and impaired endothelium-dependent vasodilation in an animal model of VILI: the role of the peroxynitrite-PARP pathway

Poly(ADP-ribosyl)ation in asthma and other lung diseases

Effects of poly(ADP-ribose) polymerase inhibition on inflammatory cell migration in a murine model of asthma

Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors

PARP-1 inhibitor, DPQ, attenuates LPS-induced acute lung injury through inhibiting NF-κB-mediated inflammatory response

Utilizing integrating network pharmacological approaches to investigate the potential mechanism of Ma Xing Shi Gan Decoction in treating COVID-19

Evidence for Gastrointestinal Infection of SARS-CoV-2

PARP-1 mediated cell death is directly activated by ZIKV infection

Poly(ADP-ribose) polymerase-1 (PARP-1) pharmacogenetics, activity and expression analysis in cancer patients and healthy volunteers

The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

SARS-CoV nucleocapsid protein induced apoptosis of COS-1 mediated by the mitochondrial pathway

COVID-19: Melatonin as a potential adjuvant treatment

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

A Novel Coronavirus from Patients with Pneumonia in China