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1.
Immunol Res ; 70(3): 269-275, 2022 06.
Article in English | MEDLINE | ID: covidwho-1889039

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A single-stranded RNA virus from a ß-Coronaviridae family causes acute clinical manifestations. Its high death rate and severe clinical symptoms have turned it into the most significant challenge worldwide. Up until now, several effective COVID-19 vaccines have been designed and marketed, but our data on specialized therapeutic drugs for the treatment of COVID-19 is still limited. In order to synthesis virus particles, SARS-CoV-2 uses host metabolic pathways such as phosphoinositide3-kinase (PI3K)/protein kinase B (PKB, also known as AKT)/mammalian target of rapamycin (mTOR). mTOR is involved in multiple biological processes. Over-activation of the mTOR pathway improves viral replication, which makes it a possible target in COVID-19 therapy. Clinical data shows the hyperactivation of the mTOR pathway in lung tissues during respiratory viral infections. However, the exact impact of mTOR pathway inhibitors on the COVID-19 severity and death rate is yet to be thoroughly investigated. There are several mTOR pathway inhibitors. Rapamycin is the most famous inhibitor of mTORC1 among all. Studies on other respiratory viruses suggest that the therapeutic inhibitors of the mTOR pathway, especially rapamycin, can be a potential approach to anti-SARS-CoV-2 therapy. Using therapeutic methods that inhibit harmful immune responses can open a new chapter in treating severe COVID-19 disease. We highlighted the potential contribution of PI3K/Akt/mTOR inhibitors in the treatment of COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/drug therapy , COVID-19 Vaccines , Humans , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/metabolism
3.
Int J Mol Med ; 49(3)2022 Mar.
Article in English | MEDLINE | ID: covidwho-1643661

ABSTRACT

The pandemic caused by the severe acute respiratory syndrome coronavirus (SARS­CoV­2), responsible for coronavirus disease 2019 (COVID­19) has posed a major challenge for global health. In order to successfully combat SARS­CoV­2, the development of effective COVID­19 vaccines is crucial. In this context, recent studies have highlighted a high COVID­19 mortality rate in patients affected by ß­thalassemia, probably due to their co­existent immune deficiencies. In addition to a role in the severity of SARS­CoV­2 infection and in the mortality rate of COVID­19­infected patients with thalassemia, immunosuppression is expected to deeply affect the effectivity of anti­COVID­19 vaccines. In the context of the interplay between thalassemia­associated immunosuppression and the effectiveness of COVID­19 vaccines, the employment of immunomodulatory molecules is hypothesized. For instance, short­term treatment with mammalian target of rapamycin inhibitors (such as everolimus and sirolimus) has been found to improve responses to influenza vaccination in adults, with benefits possibly persisting for a year following treatment. Recently, sirolimus has been considered for the therapy of hemoglobinopathies (including ß­thalassemia). Sirolimus induces the expression of fetal hemoglobin (and this may contribute to the amelioration of the clinical parameters of patients with ß­thalassemia) and induces autophagy (thereby reducing the excessive levels of α­globin). It may also finally contribute to the mobilization of erythroid cells from the bone marrow (thereby reducing anemia). In the present study, the authors present the hypothesis that sirolimus treatment, in addition to its beneficial effects on erythroid­related parameters, may play a crucial role in sustaining the effects of COVID­19 vaccination in patients with ß­thalassemia. This hypothesis is based on several publications demonstrating the effects of sirolimus treatment on the immune system.


Subject(s)
COVID-19 Vaccines/therapeutic use , Sirolimus/therapeutic use , beta-Thalassemia/therapy , COVID-19/complications , COVID-19/mortality , COVID-19/pathology , COVID-19/prevention & control , Combined Modality Therapy , Humans , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Severity of Illness Index , Sirolimus/pharmacology , Treatment Outcome , Vaccination/methods , beta-Thalassemia/complications , beta-Thalassemia/immunology
5.
Hum Cell ; 34(2): 698-699, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1060392

ABSTRACT

The current COVID-19 is one of the deadliest pandemics in recent decades. In the lack of a specific treatment for this novel infection, knowing the role of cell signaling pathways in the pathogenesis of this infection could be useful in finding effective drugs against this disease. The mammalian or mechanistic target of rapamycin (mTOR) is an important cell signaling pathway that has important role in the regulation of cell growth, protein synthesis, and metabolism in reactance to upstream signals in both pathological and normal physiological conditions. Recently, some researchers have suggested the therapeutic potential of mTOR inhibitors such as rapamycin against COVID-19. However, it is important to consider the role of activation of this pathway in controlling immune system response against viral activity in drug repositioning of rapamycin and other mTOR inhibitors in SARS-CoV-2 infection.


Subject(s)
COVID-19/drug therapy , Drug Repositioning , Immune System/immunology , Signal Transduction/genetics , Sirolimus/pharmacology , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/physiology , COVID-19/immunology , Humans , Signal Transduction/physiology
7.
Chem Biol Interact ; 331: 109282, 2020 Nov 01.
Article in English | MEDLINE | ID: covidwho-816316

ABSTRACT

The novel human coronavirus-2 (HCoV-2), called SARS-CoV-2, is the causative agent of Coronavirus Induced Disease (COVID-19) and has spread causing a global pandemic. Currently, there is no vaccine to prevent infection nor any approved drug for the treatment. The development of a new drug is time-consuming and cannot be relied on as a solution in combatting the immediate global challenge. In such a situation, the drug repurposing becomes an attractive solution to identify the potential of COVID-19 treatment by existing drugs, which are approved for other indications. Here, we review the potential use of rapamycin, an mTOR (Mammalian Target of Rapamycin) inhibitor that can be repurposed at low dosages for the treatment of COVID-19. Rapamycin inhibits protein synthesis, delays aging, reduces obesity in animal models, and inhibits activities or expression of pro-inflammatory cytokines such as IL-2, IL-6 and, IL-10. Overall, the use of rapamycin can help to control viral particle synthesis, cytokine storms and contributes to fight the disease by its anti-aging and anti-obesity effects. Since, rapamycin targets the host factors and not viral machinery, it represents a potent candidate for the treatment of COVID-19 than antiviral drugs as its efficacy is less likely to be dampened with high mutation rate of viral RNA. Additionally, the inhibitory effect of rapamycin on cell proliferation may aid in reducing viral replication. Therefore, by drug repurposing, low dosages of rapamycin can be tested for the potential treatment of COVID-19/SARS-CoV-2 infection.


Subject(s)
Coronavirus Infections/drug therapy , Drug Repositioning , Pneumonia, Viral/drug therapy , Sirolimus/therapeutic use , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , COVID-19 , Cell Proliferation/drug effects , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/metabolism , Gene Expression/drug effects , Humans , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Virus Replication/drug effects
8.
Gastroenterol Hepatol ; 43(8): 457-463, 2020 Oct.
Article in English, Spanish | MEDLINE | ID: covidwho-639589

ABSTRACT

SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Immunosuppressive Agents/adverse effects , Liver Transplantation , Pandemics , Pneumonia, Viral/epidemiology , Adaptive Immunity , Antiviral Agents/pharmacology , Betacoronavirus/immunology , Betacoronavirus/physiology , COVID-19 , Calcineurin Inhibitors/adverse effects , Calcineurin Inhibitors/pharmacology , Calcineurin Inhibitors/therapeutic use , Contraindications, Drug , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Disease Susceptibility , Drug Interactions , Everolimus/adverse effects , Everolimus/pharmacology , Everolimus/therapeutic use , Glucocorticoids/adverse effects , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Humans , Immunity, Innate , Immunocompromised Host , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Mycophenolic Acid/adverse effects , Mycophenolic Acid/pharmacology , Mycophenolic Acid/therapeutic use , Pneumonia, Viral/immunology , Postoperative Complications/immunology , Postoperative Complications/prevention & control , SARS-CoV-2 , Sirolimus/adverse effects , Sirolimus/pharmacology , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors
9.
Aging (Albany NY) ; 12(11): 10004-10021, 2020 06 12.
Article in English | MEDLINE | ID: covidwho-595737

ABSTRACT

COVID-19 is not deadly early in life, but mortality increases exponentially with age, which is the strongest predictor of mortality. Mortality is higher in men than in women, because men age faster, and it is especially high in patients with age-related diseases, such as diabetes and hypertension, because these diseases are manifestations of aging and a measure of biological age. At its deepest level, aging (a program-like continuation of developmental growth) is driven by inappropriately high cellular functioning. The hyperfunction theory of quasi-programmed aging explains why COVID-19 vulnerability (lethality) is an age-dependent syndrome, linking it to other age-related diseases. It also explains inflammaging and immunosenescence, hyperinflammation, hyperthrombosis, and cytokine storms, all of which are associated with COVID-19 vulnerability. Anti-aging interventions, such as rapamycin, may slow aging and age-related diseases, potentially decreasing COVID-19 vulnerability.


Subject(s)
Aging , Coronavirus Infections/mortality , Pneumonia, Viral/mortality , Animals , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , COVID-19 , Cellular Senescence , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Cytokines/metabolism , Disease Susceptibility , Humans , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Sirolimus/pharmacology , Sirolimus/therapeutic use
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