Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome

Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here, we used an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2. Focusing on proteins targeted by FDA-approved drugs led to three promising targets, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR). The drugs targeting these three proteins (Pacritinib, DMF, and EPO) were able to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types, and appeared to converge on Nuclear Factor Kappa B (NF-κB) signaling in inflammation. This study highlights the potential of comparative genomics to accelerate drug discovery, and yields potential new avenues for the treatment of RTT.

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Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome

10.1101/2021.02.14.431162 ◽

2021 ◽

Author(s):

Irene Unterman ◽

Idit Bloch ◽

Simona Cazacu ◽

Gila Kazimirsky ◽

Benjamin P. Berman ◽

...

Keyword(s):

Comparative Genomics ◽

Rett Syndrome ◽

Cell Types ◽

Evolutionary Genomics ◽

Mecp2 Gene ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Human Neural Cell ◽

Eukaryotic Genomes ◽

Inactivating Mutations

AbstractInactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here we use an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1,028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2. Focusing on proteins targeted by FDA approved drugs led to three promising candidates, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR). We show that each of these compounds has the ability to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types, and appear to act on Nuclear Factor Kappa B (NF-κB) signaling in inflammation. This study highlights the potential of comparative genomics to accelerate drug discovery, and yields potential new avenues for the treatment of RTT.Abstract Figure

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Fluoroquinolone Antibiotics Exhibit Low Antiviral Activity against SARS-CoV-2 and MERS-CoV

Viruses ◽

10.3390/v13010008 ◽

2020 ◽

Vol 13 (1) ◽

pp. 8

Author(s):

Stacey L. P. Scroggs ◽

Danielle K. Offerdahl ◽

Dylan P. Flather ◽

Ciera N. Morris ◽

Benjamin L. Kendall ◽

...

Keyword(s):

Cultured Cells ◽

Respiratory Infections ◽

A549 Cells ◽

Cell Types ◽

Vero Cells ◽

Cellular Toxicity ◽

Antiviral Therapies ◽

Fluoroquinolone Antibiotics ◽

Approved Drugs ◽

Fda Approved Drugs

Repurposing FDA-approved drugs that treat respiratory infections caused by coronaviruses, such as SARS-CoV-2 and MERS-CoV, could quickly provide much needed antiviral therapies. In the current study, the potency and cellular toxicity of four fluoroquinolones (enoxacin, ciprofloxacin, levofloxacin, and moxifloxacin) were assessed in Vero cells and A549 cells engineered to overexpress ACE2, the SARS-CoV-2 entry receptor. All four fluoroquinolones suppressed SARS-CoV-2 replication at high micromolar concentrations in both cell types, with enoxacin demonstrating the lowest effective concentration 50 value (EC50) of 126.4 μM in Vero cells. Enoxacin also suppressed the replication of MERS-CoV-2 in Vero cells at high micromolar concentrations. Cellular toxicity of levofloxacin was not found in either cell type. In Vero cells, minimal toxicity was observed following treatment with ≥37.5 μM enoxacin and 600 μM ciprofloxacin. Toxicity in both cell types was detected after moxifloxacin treatment of ≥300 μM. In summary, these results suggest that the ability of fluoroquinolones to suppress SARS-CoV-2 and MERS-CoV replication in cultured cells is limited.

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Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

10.1101/2021.01.31.428851 ◽

2021 ◽

Author(s):

Adam Pickard ◽

Ben C. Calverley ◽

Joan Chang ◽

Richa Garva ◽

Yinhui Lu ◽

...

Keyword(s):

Drug Repurposing ◽

Cell Types ◽

Human Hepatocytes ◽

Human Cells ◽

Proximal Tubule Cells ◽

Kidney Glomerulus ◽

Infected Cells ◽

Repurposed Drugs ◽

Approved Drugs ◽

Fda Approved Drugs

ABSTRACTCOVID-19 vaccines based on the Spike protein of SARS-CoV-2 have been developed that appear to be largely successful in stopping infection. However, vaccine escape variants might arise leading to a re-emergence of COVID. In anticipation of such a scenario, the identification of repurposed drugs that stop SARS-CoV-2 replication could have enormous utility in stemming the disease. Here, using a nano-luciferase tagged version of the virus (SARS-CoV-2- DOrf7a-NLuc) to quantitate viral load, we evaluated a range of human cell types for their ability to be infected and support replication of the virus, and performed a screen of 1971 FDA-approved drugs. Hepatocytes, kidney glomerulus, and proximal tubule cells were particularly effective in supporting SARS-CoV-2 replication, which is in- line with reported proteinuria and liver damage in patients with COVID-19. We identified 35 drugs that reduced viral replication in Vero and human hepatocytes when treated prior to SARS-CoV-2 infection and found amodiaquine, atovaquone, bedaquiline, ebastine, LY2835219, manidipine, panobinostat, and vitamin D3 to be effective in slowing SARS-CoV-2 replication in human cells when used to treat infected cells. In conclusion, our study has identified strong candidates for drug repurposing, which could prove powerful additions to the treatment of COVID.

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Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

PLoS Pathogens ◽

10.1371/journal.ppat.1009840 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009840

Author(s):

Adam Pickard ◽

Ben C. Calverley ◽

Joan Chang ◽

Richa Garva ◽

Sara Gago ◽

...

Keyword(s):

Drug Repurposing ◽

Cell Types ◽

Vero Cells ◽

Human Cells ◽

Proximal Tubule Cells ◽

Kidney Glomerulus ◽

Infected Cells ◽

Repurposed Drugs ◽

Approved Drugs ◽

Fda Approved Drugs

COVID-19 vaccines based on the Spike protein of SARS-CoV-2 have been developed that appear to be largely successful in stopping infection. However, therapeutics that can help manage the disease are still required until immunity has been achieved globally. The identification of repurposed drugs that stop SARS-CoV-2 replication could have enormous utility in stemming the disease. Here, using a nano-luciferase tagged version of the virus (SARS-CoV-2-ΔOrf7a-NLuc) to quantitate viral load, we evaluated a range of human cell types for their ability to be infected and support replication of the virus, and performed a screen of 1971 FDA-approved drugs. Hepatocytes, kidney glomerulus, and proximal tubule cells were particularly effective in supporting SARS-CoV-2 replication, which is in-line with reported proteinuria and liver damage in patients with COVID-19. Using the nano-luciferase as a measure of virus replication we identified 35 drugs that reduced replication in Vero cells and human hepatocytes when treated prior to SARS-CoV-2 infection and found amodiaquine, atovaquone, bedaquiline, ebastine, LY2835219, manidipine, panobinostat, and vitamin D3 to be effective in slowing SARS-CoV-2 replication in human cells when used to treat infected cells. In conclusion, our study has identified strong candidates for drug repurposing, which could prove powerful additions to the treatment of COVID.

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Comparing the Metabolome of a Caribbean Sponge to 420 FDA Approved Drugs, a Molecular Networking Approach

Planta Medica ◽

10.1055/s-0033-1348616 ◽

2013 ◽

Vol 79 (10) ◽

Author(s):

H Houson ◽

J Schlesser ◽

J Beverage ◽

V Macherla ◽

E Esquenazi

Keyword(s):

Molecular Networking ◽

Approved Drugs ◽

Fda Approved Drugs

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Faculty Opinions recommendation of Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718495519.793497730 ◽

2014 ◽

Author(s):

Herbert Tanowitz ◽

Fabiana Machado

Keyword(s):

Trypanosoma Cruzi ◽

Drug Combinations ◽

Potent Drug ◽

Approved Drugs ◽

Synergy Testing ◽

Fda Approved Drugs

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Faculty Opinions recommendation of Combining Molecular Scaffolds from FDA Approved Drugs: Application to Drug Discovery.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727088776.793526189 ◽

2016 ◽

Author(s):

John Lowe

Keyword(s):

Drug Discovery ◽

Molecular Scaffolds ◽

Approved Drugs ◽

Fda Approved Drugs

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Targeting COVID-19 in Parkinson’s patients: Drugs repurposed.

Current Medicinal Chemistry ◽

10.2174/0929867327666200903115138 ◽

2020 ◽

Vol 27 ◽

Author(s):

Firoz Anwar ◽

Salma Naqvi ◽

Fahad A. Al-Abbasi ◽

Nauroz Neelofar ◽

Vikas Kumar ◽

...

Keyword(s):

Day Treatment ◽

Treatment Options ◽

Developed Countries ◽

Methyl Transferase ◽

Comt Inhibitors ◽

Mao B ◽

Pharmacokinetic Properties ◽

Us Fda ◽

Approved Drugs ◽

Fda Approved Drugs

: The last couple of months have witnessed the world in a state of virtual standstill. The SARS-CoV-2 virus has overtaken globe to economic and social lockdown. Many patients with COVID-19 have compromised immunity, especially in an aged population suffering from Parkinson disease (PD). Alteration in dopaminergic neurons or deficiency of dopamine in PD patients is the most common symptoms affecting 1% population above the age of 60 years. The compromised immune system and inflammatory manifestation in PD patients make them an easy target. The most common under trial drugs for COVID-19 are Remdesivir, Favipiravir, Chloroquine and Hydroxychloroquine, Azithromycin along with adjunct drugs like Amantadine with some monoclonal antibodies. : Presently, clinically US FDA approved drugs in PD includes Levodopa, catechol-O-methyl transferase (COMT) inhibitors, (Entacapone and Tolcapone), Dopamine agonists (Bromocriptine, Ropinirole, Pramipexole, and Rotigotine), Monoamine oxidase B (MAO-B) inhibitors (Selegiline and Rasagiline), Amantadine and Antimuscarinic drugs. The drugs have established mechanism of action on PD patients with known pharmacodynamics and pharmacokinetic properties along with dose and adverse effects. : Conclusion and relevance of this review focus on the drugs that can be tried for the PD patients with SAR CoV-2 infection, in particular, Amantadine approved by all developed countries a common drug possessing both antiviral properties by downregulation of CTSL, lysosomal pathway disturbance and change in pH necessary to uncoat the viral proteins and antiParkinson properties. The significant prognostic adverse effect of SARS-CoV-2 on PD and the present-day treatment options, clinical presentation and various mechanism is warrant need of the hour.

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Pd Catalyzed N1/N4 Arylation of Piperazine for Synthesis of Drugs, Biological and Pharmaceutical Targets: An Overview of Buchwald Hartwig Amination Reaction of Piperazine in Drug Synthesis

Current Organic Synthesis ◽

10.2174/1570179415666171206151603 ◽

2018 ◽

Vol 15 (2) ◽

pp. 208-220 ◽

Cited By ~ 3

Author(s):

Vaibhav Mishra ◽

Tejpal Singh Chundawat

Keyword(s):

Bond Formation ◽

Catalyst Design ◽

Biologically Active ◽

Reaction Conditions ◽

Biological Targets ◽

Amination Reaction ◽

Drug Synthesis ◽

Substituted Piperazine ◽

Approved Drugs ◽

Fda Approved Drugs

Background: Substituted piperazine heterocycles are among the most significant structural components of pharmaceuticals. N1/N4 substituted piperazine containing drugs and biological targets are ranked 3rd in the top most frequent nitrogen heterocycles in U.S. FDA approved drugs. The high demand of N1/N4 substituted piperazine containing biologically active compounds and U.S. FDA approved drugs, has prompted the development of Pd catalyzed C-N bond formation reactions for their synthesis. Buchwald-Hartwig reaction is the key tool for the synthesis of these compounds. Objective: This review provides strategies for Pd catalyzed C-N bond formation at N1/N4 of piperazine in the synthesis of drugs and biological targets with diverse use of catalyst-ligand system and reaction parameters. Conclusion: It is clear from the review that a vast amount of work has been done in the synthesis of N1/N4 substituted piperazine containing targets under the Pd catalyzed Buchwald-Hartwig amination of aryl halides by using different catalyst-ligand systems. These methods have become increasingly versatile as a result of innovation in catalyst design and improvements in reaction conditions. This review gives an overview of recent utilization of Buchwald-Hartwig amination reaction in drug/target synthesis.

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