ABSTRACT
SARS-CoV-2 is a serious viral pathogen, and agents that inhibit its replication are in high demand. In the present work, we prepared two novel tryptanthrin derivates bearing a thiosemicarbazone moiety as potential antiviral agents. Both compounds displayed potent chelation activity against Fe(III/II) ion-associated COVID-19. The molecular docking results suggest that the compounds can display significant affinity towards SARS-CoV-2 papain-like proteases and SARS-CoV-2 main proteases. In addition, administering T8H-TSC can repress viral replication in the used model (Vero cells). Moreover, the therapeutic potential of the prepared compounds was predicted and analysed in terms of Lipinski's rules, drug-likeness and drug score.
ABSTRACT
Interleukin 6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development, wound healing and ageing, inflammation, and immunity, including COVID-19. In this review, we summarise the role of IL-6 signalling pathways in cancer biology, with particular emphasis on cancer cell invasiveness and metastasis formation. Targeting principal components of IL-6 signalling (e.g., IL-6Rs, gp130, STAT3, NF-κB) is an intensively studied approach in preclinical cancer research. It is of significant translational potential; numerous studies strongly imply the remarkable potential of IL-6 signalling inhibitors, especially in metastasis suppression.
Subject(s)
Antineoplastic Agents , COVID-19 , Neoplasms , Humans , Interleukin-6/metabolism , Neoplasms/drug therapy , Signal Transduction , Antineoplastic Agents/therapeutic useABSTRACT
Recent evidence indicates that targeting IL-6 provides broad therapeutic approaches to several diseases. In patients with cancer, autoimmune diseases, severe respiratory infections [e.g. coronavirus disease 2019 (COVID-19)] and wound healing, IL-6 plays a critical role in modulating the systemic and local microenvironment. Elevated serum levels of IL-6 interfere with the systemic immune response and are associated with disease progression and prognosis. As already noted, monoclonal antibodies blocking either IL-6 or binding of IL-6 to receptors have been used/tested successfully in the treatment of rheumatoid arthritis, many cancer types, and COVID-19. Therefore, in the present review, we compare the impact of IL-6 and anti-IL-6 therapy to demonstrate common (pathological) features of the studied diseases such as formation of granulation tissue with the presence of myofibroblasts and deposition of new extracellular matrix. We also discuss abnormal activation of other wound-healing-related pathways that have been implicated in autoimmune disorders, cancer or COVID-19.
Subject(s)
Autoimmune Diseases , COVID-19 , Neoplasms , Humans , Autoimmunity , Inflammation , Autoimmune Diseases/drug therapy , Neoplasms/drug therapy , Wound Healing , Tumor MicroenvironmentABSTRACT
COVID-19 is a pandemic respiratory disease caused by the SARS-CoV-2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient's death. This article summarizes the current knowledge regarding the potential effect of estrogens and other modulators of estrogen receptors on COVID-19. While estrogen receptor activation shows complex effects on the patient's organism, such as an influence on the cardiovascular/pulmonary/immune system which includes lower production of cytokines responsible for the cytokine storm, the receptor-independent effects directly inhibits viral replication. Furthermore, it inhibits the interaction of IL-6 with its receptor complex. Interestingly, in addition to natural hormones, phytestrogens and even synthetic molecules are able to interact with the estrogen receptor and exhibit some anti-COVID-19 activity. From this point of view, estrogen receptor modulators have the potential to be included in the anti-COVID-19 therapeutic arsenal.
Subject(s)
COVID-19/pathology , Estrogen Receptor Modulators/pharmacology , SARS-CoV-2/drug effects , Breast Neoplasms/complications , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , COVID-19/complications , COVID-19/virology , Estrogen Receptor Modulators/metabolism , Estrogen Receptor Modulators/therapeutic use , Female , Humans , Receptors, Estrogen/chemistry , Receptors, Estrogen/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Viral Matrix Proteins/antagonists & inhibitors , Viral Matrix Proteins/metabolism , Virus Internalization/drug effects , Virus Replication/drug effectsABSTRACT
Interleukin-6 (IL-6) is a cytokine with multifaceted effects playing a remarkable role in the initiation of the immune response. The increased level of this cytokine in the elderly seems to be associated with the chronic inflammatory setting of the microenvironment in aged individuals. IL-6 also represents one of the main signals in communication between cancer cells and their non-malignant neighbours within the tumour niche. IL-6 also participates in the development of a premetastatic niche and in the adjustment of the metabolism in terminal-stage patients suffering from a malignant disease. IL-6 is a fundamental factor of the cytokine storm in patients with severe COVID-19, where it is responsible for the fatal outcome of the disease. A better understanding of the role of IL-6 under physiological as well as pathological conditions and the preparation of new strategies for the therapeutic control of the IL-6 axis may help to manage the problems associated with the elderly, cancer, and serious viral infections.