Abstract
In March 2020, the World Health Organization declared the severe acute respiratory syndrome corona virus 2 (SARS-CoV2) infection to be a pandemic disease. SARS-CoV2 was first identified in China and, despite the restrictive measures adopted, the epidemic has spread globally, becoming a pandemic in a very short time. Though there is growing knowledge of the SARS-CoV2 infection and its clinical manifestations, an effective cure to limit its acute symptoms and its severe complications has not yet been found. Given the worldwide health and economic emergency issues accompanying this pandemic, there is an absolute urgency to identify effective treatments and reduce the post infection outcomes. In this context, phosphodiesterases (PDEs), evolutionarily conserved cyclic nucleotide (cAMP/cGMP) hydrolyzing enzymes, could emerge as new potential targets. Given their extended distribution and modulating role in nearly all organs and cellular environments, a large number of drugs (PDE inhibitors) have been developed to control the specific functions of each PDE family. These PDE inhibitors have already been used in the treatment of pathologies that show clinical signs and symptoms completely or partially overlapping with post-COVID-19 conditions (e.g., thrombosis, inflammation, fibrosis), while new PDE-selective or pan-selective inhibitors are currently under study. This review discusses the state of the art of the different pathologies currently treated with phosphodiesterase inhibitors, highlighting the numerous similarities with the disorders linked to SARS-CoV2 infection, to support the hypothesis that PDE inhibitors, alone or in combination with other drugs, could be beneficial for the treatment of COVID-19.
Highlights
Coronavirus disease 19 (COVID-19) is caused by infection with the severe acute respiratory syndrome corona virus 2 (SARS-CoV2), a virus belonging to the vast family of coronaviruses, responsible for illnesses ranging from the common winter cold to more serious diseases, such as the Middle East respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS) [1]
It follows that the high levels of inflammatory cytokines, such as inteleukin-6 (IL-6), tumor necrosis factor (TNF), interleukin-1 (IL-1), chemokines and the prognostic significance of IL-6 levels provide a solid rationale for adopting strategies that include treatment with anti-IL-6 monoclonal antibodies or anti-IL-16R (e.g., Tocilizumab), anti-IL-1 (e.g., Canakinumab), recombinant IL-1 receptor antagonist or inhibitors of cytokine signaling pathways, such as janus kinases 1 and 2 (JAK1,2)
There are numerous research studies that support the use of PDE inhibitors, in particular the use of inhibitors of isoforms 4 and 5, in pathologies associated with COVID-19, mostly thanks to their well-documented anti-fibrotic and anti-inflammatory effects
Summary
Coronavirus disease 19 (COVID-19) is caused by infection with the severe acute respiratory syndrome corona virus 2 (SARS-CoV2), a virus belonging to the vast family of coronaviruses, responsible for illnesses ranging from the common winter cold to more serious diseases, such as the Middle East respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS) [1]. Inhibition of excessive inflammation is a fundamental action to avoid the spreading of damage in tissues in SARS, and probably in COVID-19 It follows that the high levels of inflammatory cytokines, such as inteleukin-6 (IL-6), tumor necrosis factor (TNF), interleukin-1 (IL-1), chemokines and the prognostic significance of IL-6 levels provide a solid rationale for adopting strategies that include treatment with anti-IL-6 monoclonal antibodies or anti-IL-16R (e.g., Tocilizumab), anti-IL-1 (e.g., Canakinumab), recombinant IL-1 receptor antagonist (anakinra) or inhibitors of cytokine signaling pathways, such as janus kinases 1 and 2 (JAK1,2) (e.g., baricitinib). Similar repercussions had already been observed in people affected by SARS, who showed clearly visible anomalies associated with reduced lung volume and breathing capacity six months after infection [17] In light of these observations, thwarting the development of pulmonary fibrosis after COVID-19 recovery could be of great interest for public health. At the moment the long-term lung repercussions of COVID-19 remain speculative and require adequate prospective studies, the huge number of individuals affected by COVID-19 suggests that this aspect should not be underestimated, since it could have serious health consequences [18,19]
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