scholarly journals Regulation of m6A Methylation as a New Therapeutic Option against COVID-19

2021 ◽  
Vol 14 (11) ◽  
pp. 1135
Author(s):  
Carla Zannella ◽  
Luca Rinaldi ◽  
Giovanni Boccia ◽  
Annalisa Chianese ◽  
Ferdinando Carlo Sasso ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Viral Infection ◽  
Broad Spectrum ◽  
Therapeutic Target ◽  
Optimal Strategy ◽  
Therapeutic Option ◽  
Selective Inhibitor ◽  
Epigenetic Mechanism ◽  
Epigenetic Machinery ◽  
Rapid Spread

The rapid spread of SARS-CoV-2 and the resulting pandemic has led to a spasmodic search for approaches able to limit the diffusion of the disease. The epigenetic machinery has aroused considerable interest in the last decades, and much evidence has demonstrated that this type of modification could regulate the early stages of viral infection. Recently it was reported that N6-methyladenosine (m6A) influences SARS-CoV-2 replication, although its role remains to be further investigated. The knockdown of enzymes involved in the m6A pathway could represent an optimal strategy to deepen the epigenetic mechanism. In the present study, we blocked the catalytic activity of the fat mass and obesity-associated protein (FTO) by using the selective inhibitor rhein. We observed a strong broad-spectrum reduction of infectivity caused by various coronaviruses, including SARS-CoV-2. This effect could be due to the modulation of m6A levels and could allow identification of this modification as a new therapeutic target to treat SARS-CoV-2 infection.

scholarly journals SKLB-23bb, A HDAC6-Selective Inhibitor, Exhibits Superior and Broad-Spectrum Antitumor Activity via Additionally Targeting Microtubules

2018 ◽  
Vol 17 (4) ◽  
pp. 763-775 ◽  
Author(s):  
Fang Wang ◽  
Li Zheng ◽  
Yuyao Yi ◽  
Zhuang Yang ◽  
Qiang Qiu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Broad Spectrum ◽  
Selective Inhibitor

The Role of Sialylation in Respiratory Viral Infection and Treatment

2021 ◽  
Vol 28 ◽  
Author(s):  
Harrison Steele ◽  
Andrew J. Tague ◽  
Danielle Skropeta
Keyword(s):  
Viral Infection ◽  
Broad Spectrum ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Sialic Acids ◽  
Infection Cycle ◽  
Respiratory Viral Infection ◽  
Development Of Resistance ◽  
High Infection ◽  
Cell Expression

: Respiratory infections caused by viruses such as influenza and coronavirus are a serious global problem due to their high infection rates and potential to spark pandemics, such as the current COVID-19 pandemic. Although preventing these infections by using vaccines has been the most successful strategy to date, effective vaccines are not always available. Therefore, developing broad-spectrum anti-viral drugs to treat such infections is essential, especially in the case of immunocompromised patients, or for outbreaks of novel virus strains. Sialic acids have been highlighted as a key molecule in the viral infection cycle, with terminally sialylated glycans acting as a target for several viral proteins involved in infection, particularly respiratory infection. Inhibitors of one such protein, neuraminidase, are the only anti-influenza drugs currently on the market. Problems with neuraminidase inhibitors, including development of resistance and a relatively narrow spectrum of activity, drive the need for an improved understanding of the viral infection cycle and the development of more resilient, broader-spectrum anti-viral treatments. Hence, this review outlines the various roles played by sialic acids in respiratory viral infection and provides examples of drugs that exploit sialic acids to inhibit viral infections. It has been concluded that drugs targeting host cell expression of sialic acid could be especially well suited to inhibiting a broad spectrum of respiratory infections. This warrants the continued design and improvement of such drugs in an attempt to lessen the burden of respiratory infections.

Characterization of a selective inhibitor for matrix metalloproteinase-8 (MMP-8)

MedChemComm ◽  
2014 ◽  
Vol 5 (9) ◽  
pp. 1381-1383 ◽  
Author(s):  
Derong Ding ◽  
Katerina Lichtenwalter ◽  
Hualiang Pi ◽  
Shahriar Mobashery ◽  
Mayland Chang
Keyword(s):  
Matrix Metalloproteinase ◽  
Broad Spectrum ◽  
Selective Inhibitor ◽  
Mmp Inhibitor

MMP-8 has been implicated in various diseases using a reported selective MMP-8 inhibitor that is actually a broad-spectrum MMP inhibitor.

scholarly journals KCNN4 Expression Is Elevated in Inflammatory Bowel Disease: This Might Be a Novel Marker and Therapeutic Option Targeting Potassium Channels

2020 ◽  
Vol 29 (4) ◽  
pp. 539-547
Author(s):  
Christoph Süss ◽  
Lucile Broncy ◽  
Kirstin Pollinger ◽  
Claudia Kunst ◽  
Karsten Gülow ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Cell Monolayer ◽  
Secretory Diarrhea ◽  
K Channel ◽  
Epithelial Barrier ◽  
Mrna Levels ◽  
Inflammatory Bowel

Background and Aims: The K + channel KCNN4 is involved in many inflammatory diseases. Previous work has shown that this channel is involved in epithelial ion transport and intestinal restitution. In inflammatory bowel diseases (IBD) a defective epithelial barrier can lead to typical symptoms like secretory diarrhea and the formation of intestinal ulcers. We compared surgical samples from patients with IBD, diverticulitis and controls without inflammation to determine the potential role of KCNN4 as a diagnostic marker and/or therapeutic target. Methods: mRNA-levels of KCNN4 and a control K + channel were determined in intestinal epithelial cells (IEC) from patients with IBD, diverticulitis and controls. In addition, we performed a Western blot analysis of KCNN4 and a respective control K + channel in IEC from patients with IBD. Furthermore, we determined epithelial barrier integrity by measuring the flux of fluorescent-labeled dextran beads across a cell monolayer upon incubation with interferon-γ. Results: KCNN4 mRNA and protein levels were elevated in IEC from patients with Crohn`s disease (CD) and ulcerative colitis (UC). Of note, KCNN4 was not elevated in non-IBD intestinal inflammatory conditions e.g. diverticulitis. Of clinical relevance, pharmacological KCNN4 channel openers stabilized epithelial barrier function in vitro. Thus, KCNN4 may have a protective role in IBD and constitute a therapeutic target. Conclusions: Our data demonstrate elevated KCNN4 both at mRNA and protein level in IEC specifically from patients with IBD. Therefore, we conclude that KCNN4 could be used as a novel marker for IBD, especially for the establishment of initial diagnosis. Of therapeutic consequence, we show that pharmacological KCNN4 openers stabilize the epithelial barrier. Thus, KCNN4 might be a novel target to diagnose and treat IBD.

scholarly journals The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders

2019 ◽  
Author(s):  
Patrick Miller-Rhodes ◽  
Cuicui Kong ◽  
Gurpreet S. Baht ◽  
Ramona M. Rodriguiz ◽  
William C. Wetsel ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Orthopedic Surgery ◽  
Therapeutic Option ◽  
Postoperative Cognitive Dysfunction ◽  
Light Sheet ◽  
Neurocognitive Disorders ◽  
Mixed Lineage Kinase ◽  
Light Sheet Microscopy ◽  
Mixed Lineage Kinase 3 ◽  
Induced Changes

AbstractPerioperative neurocognitive disorders (PND), including delirium and postoperative cognitive dysfunction, are serious complications that afflict up to 50% of surgical patients and for which there are no disease-modifying therapeutic options. Here, we test whether prophylactic treatment with the broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents surgery-induced neuroinflammation and cognitive impairment in a translational model of orthopedic surgery-induced PND. We used a combination of two-photon scanning laser microscopy and CLARITY with light-sheet microscopy to define surgery-induced changes in microglial dynamics and morphology. Orthopedic surgery induced widespread microglial activation in the hippocampus and cortex that accompanied impairments in episodic memory. URMC-099 prophylaxis prevented these neuropathological sequelae without impacting bone fracture healing. Together, these findings provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND.

scholarly journals Fast Restoration of a Broad-Spectrum SARS-Cov Therapeutic Antibody for SARS-Cov-2

2020 ◽  
Author(s):  
Sara Zhang ◽  
Mike Young ◽  
Jason Pan
Keyword(s):  
Broad Spectrum ◽  
Neutralizing Antibodies ◽  
Global Economy ◽  
Therapeutic Antibody ◽  
Receptor Binding Domain ◽  
Promising Candidate ◽  
Rapid Spread ◽  
Antibody Design ◽  
Potential Therapeutics ◽  
Conserved Epitope

<p>The rapid spread of SARS-Cov-2 remains a major threat for public health and global economy, both preventative and therapeutic solutions are therefore urgently needed. Through the use of epitope-guided antibody design, we successfully restored a broad-spectrum SARS-Cov therapeutic antibody for SARS-Cov-2. Compared to the precursor antibody CR3022, the newly designed antibody NOVOAB-20 binds to SARS-Cov-2 receptor binding domain (RBD) with a more than 10-fold higher affinity. Because this antibody targets a highly conserved epitope and the mutations on SARS-Cov-2 known so far are all not in this region, it also has the potential to block future SARS-Cov-2 mutants. As a fully humanized antibody, NOVOAB-20 is a promising candidate to be developed as potential therapeutics for SARS-Cov-2, either as monotherapy or in combination with other neutralizing antibodies targeting different epitopes (e.g. the ACE2 binding site).</p>

Siccanin Is a Novel Selective Inhibitor of Trypanosomatid Complex II (Succinate-Ubiquinone Reductase) and a Potent Broad-Spectrum Anti-trypanosomatid Drug Candidate

2016 ◽  
pp. 101-122 ◽  
Author(s):  
Nozomu Nihashi ◽  
Daniel Ken Inaoka ◽  
Chiaki Tsuge ◽  
Emmanuel Oluwadare Balogun ◽  
Yasutaka Osada ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Selective Inhibitor ◽  
Drug Candidate ◽  
Complex Ii

scholarly journals KPC-mediated resistance to ceftazidime-avibactam and collateral effects in Klebsiella pneumoniae

2021 ◽  
Author(s):  
Jacqueline Findlay ◽  
Laurent Poirel ◽  
Mario Juhas ◽  
Patrice Nordmann
Keyword(s):  
Klebsiella Pneumoniae ◽  
Broad Spectrum ◽  
In Vitro Selection ◽  
Multidrug Resistant ◽  
Single Step ◽  
Carbapenem Resistant ◽  
Rapid Spread ◽  
Collateral Effects ◽  
Novel Drug

Carbapenem-resistant Enterobacterales, such as KPC-producing Klebsiella pneumoniae , represent a major threat to public health due to their rapid spread. Novel drug combinations such as ceftazidime-avibactam (CZA), combining a broad-spectrum cephalosporin along with a broad-spectrum ß-lactamase inhibitor, have recently been introduced and have been shown to exhibit excellent activity towards multidrug-resistant KPC-producing Enterobacterale strains. However, CZA-resistant K. pneumoniae isolates are now being increasingly reported, mostly corresponding to producers of KPC variants. In this study, we evaluated in vitro the nature of the mutations in the KPC-2 and KPC-3 ß-lactamase sequences (the most frequent KPC-type enzymes) that lead to CZA resistance, and the subsequent effects of these mutations on susceptibility to other ß-lactam antibiotics. Single-step in vitro selection assays were conducted resulting in the identification of a series of mutations in the KPC sequence which conferred the ability to those mutated enzymes to confer resistance to CZA. Hence, 16 KPC-2 variants and 10 KPC-3 variants were obtained. Production of the KPC variants in an Escherichia coli recombinant strain resulted in a concomitant increased susceptibility to broad-spectrum cephalosporins and carbapenems, with the exceptions of ceftazidime and piperacillin-tazobactam, compared to wild-type KPC enzymes. Enzymatic assays showed that all of the KPC variants identified exhibited an increased affinity toward ceftazidime and a slightly decreased sensitivity to avibactam, sustaining their impact on CZA resistance. However their respective carbapenemase activities were concurrently negatively impacted.

scholarly journals The Crosstalk of Epigenetics and Metabolism in Herpesvirus Infection

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1377
Author(s):  
Yonggang Pei ◽  
Erle S. Robertson
Keyword(s):  
Virus Infection ◽  
Viral Infection ◽  
Epigenetic Regulation ◽  
Targeted Therapies ◽  
Therapeutic Target ◽  
Human Herpesvirus ◽  
Viral Diseases ◽  
Herpesvirus Infection ◽  
Potential Therapeutic Target ◽  
The Status

Epigenetics is a versatile player in manipulating viral infection and a potential therapeutic target for the treatment of viral-induced diseases. Both epigenetics and metabolism are crucial in establishing a highly specific transcriptional network, which may promote or suppress virus infection. Human herpesvirus infection can induce a broad range of human malignancies and is largely dependent on the status of cellular epigenetics as well as its related metabolism. However, the crosstalk between epigenetics and metabolism during herpesvirus infection has not been fully explored. Here, we describe how epigenetic regulation of cellular metabolism affects herpesvirus infection and induces viral diseases. This further highlights the importance of epigenetics and metabolism during viral infection and provides novel insights into the development of targeted therapies.

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