scholarly journals The SARS-CoV-2 conserved macrodomain is a mono-ADP-ribosylhydrolase

2020 ◽  
Author(s):  
Yousef M.O. Alhammad ◽  
Maithri M. Kashipathy ◽  
Anuradha Roy ◽  
Jean-Philippe Gagné ◽  
Peter McDonald ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Therapeutic Target ◽  
Viral Infections ◽  
Protein Domain ◽  
Structural Protein ◽  
Potential Therapeutic Target ◽  
Novel Therapeutic Strategies ◽  
Design And Testing ◽  
Translational Process ◽  
Novel Therapeutic

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-related CoVs encode 3 tandem macrodomains within non-structural protein 3 (nsp3). The first macrodomain, Mac1, is conserved throughout CoVs, and binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 likely counters host-mediated anti-viral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose. SARS-CoV-2, SARS-CoV and MERS-CoV Mac1 exhibit similar structural folds and all 3 proteins bound to ADP-ribose with low μM affinities. Importantly, using ADP-ribose detecting binding reagents in both a gel-based assay and novel ELISA assays, we demonstrated de-MARylating activity for all 3 CoV Mac1 proteins, with the SARS-CoV-2 Mac1 protein leading to a more rapid loss of substrate compared to the others. In addition, none of these enzymes could hydrolyze poly-ADP-ribose. We conclude that the SARS-CoV-2 and other CoV Mac1 proteins are MAR-hydrolases with similar functions, indicating that compounds targeting CoV Mac1 proteins may have broad anti-CoV activity. IMPORTANCE SARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused greater than 1.2 million deaths worldwide. With, no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode for a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose adducts from proteins in a dynamic post-translational process increasingly recognized as an important factor that regulates viral infection. The macrodomain is essential for CoV pathogenesis and may be a novel therapeutic target. Thus, understanding its biochemistry and enzyme activity are critical first steps for these efforts. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose, and describe its ADP-ribose binding and hydrolysis activities in direct comparison to SARS-CoV and MERS-CoV Mac1 proteins. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.

scholarly journals The SARS-CoV-2 conserved macrodomain is a mono-ADP-ribosylhydrolase

2020 ◽  
Author(s):  
Yousef M.O. Alhammad ◽  
Maithri M. Kashipathy ◽  
Anuradha Roy ◽  
Jean-Philippe Gagné ◽  
Peter McDonald ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Therapeutic Target ◽  
Viral Infections ◽  
Protein Domain ◽  
Structural Protein ◽  
Potential Therapeutic Target ◽  
Novel Therapeutic Strategies ◽  
Design And Testing ◽  
Translational Process ◽  
Novel Therapeutic

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like-CoVs encode 3 tandem macrodomains within non-structural protein 3 (nsp3). The first macrodomain, Mac1, is conserved throughout CoVs, and binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 likely counters host-mediated anti-viral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose. SARS-CoV-2, SARS-CoV and MERS-CoV Mac1 exhibit similar structural folds and all 3 proteins bound to ADP-ribose with low μM affinities. Importantly, using ADP-ribose detecting binding reagents in both a gel-based assay and novel ELISA assays, we demonstrated de-MARylating activity for all 3 CoV Mac1 proteins, with the SARS-CoV-2 Mac1 protein leading to a more rapid loss of substrate compared to the others. In addition, none of these enzymes could hydrolyze poly-ADP-ribose. We conclude that the SARS-CoV-2 and other CoV Mac1 proteins are MAR-hydrolases with similar functions, indicating that compounds targeting CoV Mac1 proteins may have broad anti-CoV activity.IMPORTANCESARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused greater than 900 thousand deaths worldwide. With, no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode for a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose adducts from proteins in a dynamic post-translational process increasingly recognized as an important factor that regulates viral infection. The macrodomain is essential for CoV pathogenesis and may be a novel therapeutic target. Thus, understanding its biochemistry and enzyme activity are critical first steps for these efforts. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose, and describe its ADP-ribose binding and hydrolysis activities in direct comparison to SARS-CoV and MERS-CoV Mac1 proteins. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.

scholarly journals SIRT1: A Potential Therapeutic Target in Autoimmune Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Pan Shen ◽  
Xuan Deng ◽  
Zhe Chen ◽  
Xin Ba ◽  
Kai Qin ◽  
...  
Keyword(s):  
Immune Responses ◽  
Autoimmune Diseases ◽  
Small Molecules ◽  
Therapeutic Target ◽  
Histone Deacetylases ◽  
Sirtuin 1 ◽  
Class Iii ◽  
Potential Therapeutic Target ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

The morbidity and mortality of autoimmune diseases (Ads) have been increasing worldwide, and the identification of novel therapeutic strategies for prevention and treatment is urgently needed. Sirtuin 1 (SIRT1), a member of the class III family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in the progression of several diseases. SIRT1 also regulates inflammation, oxidative stress, mitochondrial function, immune responses, cellular differentiation, proliferation and metabolism, and its altered functions are likely involved in Ads. Several inhibitors and activators have been shown to affect the development of Ads. SIRT1 may represent a novel therapeutic target in these diseases, and small molecules or natural products that modulate the functions of SIRT1 are potential therapeutic agents. In the present review, we summarize current studies of the biological functions of SIRT1 and its role in the pathogenesis and treatment of Ads.

scholarly journals MiR-29a: a potential therapeutic target and promising biomarker in tumors

2018 ◽  
Vol 38 (1) ◽  
Author(s):  
Jin-yan Wang ◽  
Qian Zhang ◽  
Dan-dan Wang ◽  
Wei Yan ◽  
Huan-huan Sha ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Therapeutic Target ◽  
Therapeutic Strategy ◽  
Transcriptional Level ◽  
Additional Insight ◽  
Potential Therapeutic Target ◽  
Rna Molecules ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Novel Therapeutic

MiRNAs, small non-coding RNA molecules, were recognized to be associated with the incidence and development of diverse neoplasms. MiRNAs were small non-coding RNAs that could regulate post-transcriptional level by binding to 3′-UTR of target mRNAs. Amongst which, miR-29a was demonstrated that it had significant impact on oncogenicity in various neoplasms through binding to critical genes which enhanced or inhibited the progression of cancers. MiR-29a participated in kinds of physiological and pathological processes, including virus replication, cell proliferation, differentiation, apoptosis, fibrosis, angiogenesis, tumorigenicity, metastasis, drug-resistance, and so on. According to its sufficient sensitivity and specificity, many studies showed that miR-29a might serve as a potential therapeutic target and promising biomarker in various tumors. In this review, we discussed the functions of miR-29a and its potential application in the diagnosis, treatment and stages of carcinoma, which could provide additional insight to develop a novel therapeutic strategy.

scholarly journals The promise of mTOR as a therapeutic target pathway in idiopathic pulmonary fibrosis

2020 ◽  
Vol 29 (157) ◽  
pp. 200269
Author(s):  
Manuela Platé ◽  
Delphine Guillotin ◽  
Rachel C Chambers
Keyword(s):  
Extracellular Matrix ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Therapeutic Target ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Lung Parenchyma ◽  
Extracellular Signals ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Idiopathic pulmonary fibrosis (IPF) is characterised by the progressive deposition of excessive extracellular matrix proteins within the lung parenchyma and represents the most rapidly progressive and fatal of all fibrotic conditions. Current anti-fibrotic drugs approved for the treatment of IPF fail to halt disease progression and have significant side-effect profiles. Therefore, there remains a pressing need to develop novel therapeutic strategies for IPF. Mammalian target of rapamycin (mTOR) forms the catalytic subunit of two complexes, mTORC1 and mTORC2. mTORC1 acts as critical cellular sensor which integrates intracellular and extracellular signals to reciprocally regulate a variety of anabolic and catabolic processes. The emerging evidence for a critical role for mTORC1 in influencing extracellular matrix production, metabolism, autophagy and senescence in the setting of IPF highlights this axis as a novel therapeutic target with the potential to impact multiple IPF pathomechanisms.

scholarly journals BRD4 is a novel therapeutic target for liver fibrosis

2015 ◽  
Vol 112 (51) ◽  
pp. 15713-15718 ◽  
Author(s):  
Ning Ding ◽  
Nasun Hah ◽  
Ruth T. Yu ◽  
Mara H. Sherman ◽  
Chris Benner ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Fibrosis ◽  
Therapeutic Target ◽  
Stellate Cell ◽  
Fibrotic Response ◽  
Potential Therapeutic Target ◽  
Molecule Inhibitor ◽  
Extracellular Matrix Components ◽  
Matrix Components ◽  
Novel Therapeutic

Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications.

scholarly journals MiRNA Profiling in Plasma and Placenta of SARS-CoV-2-Infected Pregnant Women

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1788
Author(s):  
Irma Saulle ◽  
Micaela Garziano ◽  
Claudio Fenizia ◽  
Gioia Cappelletti ◽  
Francesca Parisi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pregnant Women ◽  
Vertical Transmission ◽  
Mirna Expression ◽  
Therapeutic Target ◽  
Immune Reaction ◽  
Viral Infections ◽  
Clinical Symptoms ◽  
Potential Therapeutic Target ◽  
Qpcr Array

MicroRNAs are gene expression regulators associated with several human pathologies, including those generated by viral infections. Their role in SARS-CoV-2 infection and COVID-19 has been investigated and reviewed in many informative studies; however, a thorough miRNA outline in SARS-CoV-2-infected pregnant women (SIPW), at both systemic and placental levels, is missing. To fill this gap, blood and placenta biopsies collected at delivery from 15 asymptomatic SIPW were immediately analysed for: miRNA expression (n = 84) (QPCR array), antiviral/immune mRNA target expression (n = 74) (QGene) and cytokine/chemokines production (n = 27) (Multiplex ELISA). By comparing these results with those obtained from six uninfected pregnant women (UPW), we observed that, following SARS-CoV-2 infection, the transcriptomic profile of pregnant women is significantly altered in different anatomical districts, even in the absence of clinical symptoms and vertical transmission. This characteristic combination of miRNA and antiviral/immune factors seems to control both the infection and the dysfunctional immune reaction, thus representing a positive correlate of protection and a potential therapeutic target against SARS-CoV-2.

scholarly journals The neutralization of heparan sulfate by heparin-binding copolymer as a potential therapeutic target

RSC Advances ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 3020-3029 ◽  
Author(s):  
Bartlomiej Kalaska ◽  
Joanna Miklosz ◽  
Kamil Kamiński ◽  
Bogdan Musielak ◽  
Shin-Ichi Yusa ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Therapeutic Target ◽  
Viral Infections ◽  
Heparin Binding ◽  
Potential Therapeutic Target

The neutralization of heparan sulfate (HS) by a heparin-binding copolymer (HBC) could be a promising treating option for bacterial or viral infections or bleeding related to overproduction of HS in cancer or other diseases.

scholarly journals Targeting of Non-Structural Protein 9 as a Novel Therapeutic Target for the Treatment of SARS-CoV-2

2020 ◽  
Vol 3 ◽  
Author(s):  
Matthew Anderson ◽  
John Turchi
Keyword(s):  
Viral Replication ◽  
Therapeutic Target ◽  
Rna Binding ◽  
Future Research ◽  
Great Promise ◽  
Dependent Manner ◽  
Nucleic Acid Binding ◽  
Structural Protein ◽  
Concentration Dependent Manner ◽  
Novel Therapeutic

Background/Hypothesis:  The 2019 novel coronavirus (SARS-CoV-2) is a human coronavirus responsible for a global pandemic with over 13 million confirmed cases. Currently, there are no treatments to block viral infection or replication. Exploring novel therapeutic targets for SARS-CoV-2 and future coronaviruses holds great promise for treating the current and future outbreaks. One such target is the non-structural protein 9 (nsp9), which has been shown to be highly conserved and unique to the coronavirus family as well as playing a role in viral replication. We hypothesize nsp9 is a viable target for therapeutic development.     Methods:  Towards determining the utility of targeting nsp9, a series of databases were queried for articles pertaining to nsp9 in SARS-CoV-2 and other coronaviruses and coronaviruses in general. We assessed structural, biochemical and cellular features of nsp9.      Results:  Nsp9 forms a homodimer via a conserved a-helix containing a glycine-rich interaction motif (GxxxG). Dimerization at the GxxxG interface is required for efficient viral replication. Nsp9’s core is an open, six-stranded b-barrel whose fold gives it a structure similar to nucleic acid binding OB-fold proteins. This OB-like fold has not been detected in replicative complexes of other RNA viruses and may reflect the unique and complex CoV replication machinery. Nsp9 is an indispensable component of the replication complex that binds single-stranded RNA in a concentration-dependent manner. A recent bioinformatic approach also found that nsp9 interacts with NF-kappa-B-repressing factor and may play a role in the IL-8/IL-6 mediated chemotaxis of neutrophils and inflammatory response observed in Covid-19 patients.     Conclusion/Potential Impact:   Based on this research, we conclude nsp9 represents a novel therapeutic target whose OB-like-fold may provide a targetable structure for interrupting RNA binding and impairing viral replication. This study will help inform current and future research that seeks to target nsp9’s structure and biochemical interactions as treatment for coronavirus infection. 

Memapsin 2, a drug target for Alzheimer's disease

2003 ◽  
Vol 70 ◽  
pp. 213-220 ◽  
Author(s):  
Gerald Koelsch ◽  
Robert T. Turner ◽  
Lin Hong ◽  
Arun K. Ghosh ◽  
Jordan Tang
Keyword(s):  
Crystal Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transition State ◽  
Amyloid Precursor Protein ◽  
Therapeutic Target ◽  
Drug Target ◽  
Aspartic Protease ◽  
Precursor Protein ◽  
Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

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