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1.
Molecules ; 27(11)2022 May 26.
Article in English | MEDLINE | ID: covidwho-1866459

ABSTRACT

Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound (S)-4h showed outstanding metabolic stability (T1/2 = 67 min) in RLM, with an IC50 of 332 nM against PDE5. Furthermore, some interesting structure-activity relationships (SAR) were explained with the assistance of molecular docking.


Subject(s)
Dipyridamole , Idiopathic Pulmonary Fibrosis , Animals , Dipyridamole/pharmacology , Dipyridamole/therapeutic use , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Microsomes, Liver/metabolism , Molecular Docking Simulation , Molecular Structure , Rats , Structure-Activity Relationship
4.
Curr Opin Chem Biol ; 65: 74-84, 2021 12.
Article in English | MEDLINE | ID: covidwho-1312961

ABSTRACT

Drug repurposing aims to find new uses for already existing and approved drugs. We now provide a brief overview of recent developments in drug repurposing using machine learning alongside other computational approaches for comparison. We also highlight several applications for cancer using kinase inhibitors, Alzheimer's disease as well as COVID-19.


Subject(s)
Alzheimer Disease/drug therapy , COVID-19/drug therapy , Drug Repositioning/trends , Machine Learning , Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , Antiviral Agents/therapeutic use , Clemastine/pharmacology , Computational Biology/methods , Dipyridamole/pharmacology , Humans , Hydroxychloroquine/pharmacology , Lenalidomide/pharmacology , Neuroprotective Agents/therapeutic use , Piperazines/pharmacology , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology
6.
Proc Natl Acad Sci U S A ; 117(44): 27381-27387, 2020 11 03.
Article in English | MEDLINE | ID: covidwho-867659

ABSTRACT

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a restraint energy distribution (RED) function, making the practical FEP-ABFE-based virtual screening of the existing drug library possible. As a result, out of 25 drugs predicted, 15 were confirmed as potent inhibitors of SARS-CoV-2 Mpro The most potent one is dipyridamole (inhibitory constant Ki = 0.04 µM) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki = 0.36 µM) and chloroquine (Ki = 0.56 µM) were also found to potently inhibit SARS-CoV-2 Mpro We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Drug Repositioning , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , COVID-19 , Chloroquine/pharmacology , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Cysteine Endopeptidases , Dipyridamole/pharmacology , Humans , Hydroxychloroquine/pharmacology , Molecular Docking Simulation , Molecular Structure , Pandemics , Pneumonia, Viral/drug therapy , SARS-CoV-2
7.
Curr Pharm Des ; 27(6): 866-875, 2021.
Article in English | MEDLINE | ID: covidwho-810094

ABSTRACT

BACKGROUND: COVID-19 pandemic is caused by coronavirus also known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The viral infection continues to impact the globe with no vaccine to prevent the infection or highly effective therapeutics to treat the millions of infected people around the world. The disease starts as a respiratory infection, yet it may also be associated with a hypercoagulable state, severe inflammation owing to excessive cytokines production, and a potentially significant oxidative stress. The disease may progress to multiorgan failure and eventually death. OBJECTIVE: In this article, we summarize the potential of dipyridamole as an adjunct therapy for COVID-19. METHODS: We reviewed the literature describing the biological activities of dipyridamole in various settings of testing. Data were retrieved from PubMed, SciFinder-CAS, and Web of Science. The review concisely covered relevant studies starting from 1977. RESULTS: Dipyridamole is an approved antiplatelet drug, that has been used to prevent stroke, among other indications. Besides its antithrombotic activity, the literature indicates that dipyridamole also promotes a host of other biological activities including antiviral, anti-inflammatory, and antioxidant ones. CONCLUSION: Dipyridamole may substantially help improve the clinical outcomes of COVID-19 treatment. The pharmacokinetics profile of the drug is well established which makes it easier to design an appropriate therapeutic course. The drug is also generally safe, affordable, and available worldwide. Initial clinical trials have shown a substantial promise for dipyridamole in treating critically ill COVID-19 patients, yet larger randomized and controlled trials are needed to confirm this promise.


Subject(s)
COVID-19 , Pandemics , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Dipyridamole , Humans , SARS-CoV-2
9.
Med Hypotheses ; 143: 110051, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-624899

ABSTRACT

Counterproductive lung inflammation and dysregulated thrombosis contribute importantly to the lethality of advanced COVID-19. Adenosine A2A receptors (A2AR), expressed by a wide range of immune cells, as well as endothelial cells and platelets, exert cAMP-mediated anti-inflammatory and anti-thrombotic effects that potentially could be highly protective in this regard. The venerable drug pentoxifylline (PTX) exerts both anti-inflammatory and antithrombotic effects that reflect its ability to boost the responsiveness of A2AR to extracellular adenosine. The platelet-stabilizing drug dipyridamole (DIP) blocks intracellular uptake of extracellularly-generated adenosine, thereby up-regulating A2AR signaling in a way that should be functionally complementary to the impact of PTX in that regard. Moreover, DIP has recently been reported to slow the cellular replication of SARS-CoV-2 in clinically feasible concentrations. Both PTX and DIP are reasonably safe, well-tolerated, widely available, and inexpensive drugs. When COVID-19 patients can be treated within several days of symptom onset, using PTX + DIP in conjunction with hydroxychloroquine (HCQ) and an antibiotic - azithromycin (AZM) or doxycycline - might be warranted. HCQ and AZM can suppress SARS-CoV-2 proliferation in vitro and may slow the cell-to-cell spread of the virus; a large case series evaluating this combination in early-stage patients reported an impressively low mortality rate. However, whereas HCQ and AZM can promote QT interval lengthening and may be contraindicated in more advanced COVID-19 entailing cardiac damage, doxycycline has no such effect and exerts a potentially beneficial anti-inflammatory action. In contrast to HCQ, we propose that the combination of PTX + DIP can be used in both early and advanced stages of COVID-19. Concurrent use of certain nutraceuticals - yeast beta-glucan, zinc, vitamin D, spirulina, phase 2 inducers, N-acetylcysteine, glucosamine, quercetin, and magnesium - might also improve therapeutic outcomes in COVID-19.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Dipyridamole/therapeutic use , Pandemics , Pentoxifylline/therapeutic use , Pneumonia, Viral/drug therapy , Receptor, Adenosine A2A/metabolism , Adenosine A2 Receptor Agonists/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/metabolism , Dietary Supplements , Fibrinolytic Agents/therapeutic use , Humans , Models, Biological , Pneumonia/etiology , Pneumonia/prevention & control , Pneumonia, Viral/complications , Pneumonia, Viral/metabolism , SARS-CoV-2 , Signal Transduction/drug effects , Thrombosis/etiology , Thrombosis/prevention & control , Virus Replication/drug effects
10.
Emerg Microbes Infect ; 9(1): 1514-1522, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-611844

ABSTRACT

We previously made the hypothesis that STING contributes to COVID-19. The present review detail new arguments for over-activation of STING pathways in COVID-19, following the description of hyper-coagulability and Kawasaki-like diseases in children. Indeed, Kawasaki disease is induced by overreaction of innate cells following exposition to various viruses, including herpes viruses which trigger STING. It predisposes to diffuse vasculitis and aneurysms, whereas STING is over-expressed in arterial aneurisms. The redness at the inoculation site of bacillus Calmette-Guérin, a specific feature of Kawasaki disease, is reproduced by activation of the STING pathway, which is inhibited upstream by aspirin, intravenous immunoglobulins, and Vitamin-D. SARS-CoV2 binding to ACE2 can lead to excessive angiotensin II signaling, which activates the STING pathway in mice. Over-activation of the STING-pathway promotes hyper-coagulability through release of interferon-ß and tissue factor by monocytes-macrophages. Aspirin and dipyridamole, besides their anti-platelet activity, also reduce tissue factor procoagulant activity, and aspirin inhibits the STING pathway upstream of STING. Aspirin and dipyridamole may be used, in combination with drugs blocking downstream the activation of the STING pathway, like inhibitors of IL-6R and JAK/STAT pathways. The risk of bleeding should be low as bleeding has not been reported in severe COVID-19 patients.


Subject(s)
Coronavirus Infections/complications , Membrane Proteins/metabolism , Mucocutaneous Lymph Node Syndrome/etiology , Pneumonia, Viral/complications , Angiotensin II/metabolism , Animals , Aspirin/therapeutic use , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/metabolism , Blood Coagulation Disorders/virology , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Dipyridamole/therapeutic use , Humans , Immunoglobulins, Intravenous/therapeutic use , Interferons/metabolism , Mice , Mucocutaneous Lymph Node Syndrome/metabolism , Pandemics , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Signal Transduction , Thrombosis/drug therapy , Thrombosis/metabolism , Thrombosis/virology
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