Phosphodiesterase Inhibitors: Could They Be Beneficial for the Treatment of COVID-19?

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.

PDE3-inhibitor enoximone prevented mechanical ventilation in patients with SARS-CoV-2 pneumonia

“…29 Therefore, it is worthwhile to explore safer treatment options with comparable anti-inflammatory effects. 11 PDE inhibitors might have potential in the treatment of COVID-19, 30 mainly through antiinflammatory effects resulting from PDE3 and/or PDE4 inhibition by reducing cytokines including TNF-a levels. 11,31,32 Additionally, PDE3 inhibitors are potent bronchodilators through relaxation of the airway smooth muscle cells and reduces pulmonary edema.…”

“…This may obviously help shorten the trajectory of registration for new indications. In clinical trial.gov and published papers, 30 several studies with existing (classes of) off-label drugs for COVID-19 have been initiated/proposed, with different strategies and targets, including virus replication, inflammatory sequelae, pulmonary capillary leakage and/or thrombo-embolic events. Targeting the complex SARS-CoV-2 cascade at different levels seems rational.…”

“…Hence systemic application of PDE3-inhibitors in COVID-19 seems plausible, given the wide scope of targets for this drug class within the complex pathophysiology of this syndrome. 5,23,30 Obviously this requires further research.…”

Phosphodiesterase Inhibitors in Acute Lung Injury: What Are the Perspectives?

“…Recent data show that both nonselective and selective PDE inhibitors might be useful in ARDS caused by a severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) leading to COVID-19. Current knowledge on the pathophysiology of COVID-19 and participation of the cyclic nucleotide pathways in inflammation, fibrosis, vascular resistance, thrombosis, and stroke have been recently published by Giorgi et al in their excellent review [ 194 ]. In this chapter, we present a short overview of those COVID-associated changes related to PDEs and provide the data about ongoing clinical studies where the PDE inhibitors have been administered to patients with COVID-19-induced ARDS.…”

“…However, binding of SARS-CoV2 with ACE2 receptor downregulates the ACE2 expression, which increases the levels of angiotensin II exerting the above mentioned deleterious effects to the lung [ 199 ]. In addition, binding of SARS-CoV virus on the ACE2 receptors triggers an activation of innate immune reaction to combat an infection, with an activation of various immune cells and a production of enormous concentrations of cytokines, so-called cytokine storm [ 194 ]. In the pathophysiology of the SARS-CoV2-induced ARDS, IL-6 is of a particular importance; it promotes a clearance of the virus by neutrophils, triggers an accumulation of fluid and immune cells including neutrophils in the lung, causes a serious endothelial dysfunction, and induces an intestinal, olfactory, ocular inflammation causing diarrhea, anosmia, and conjunctivitis, the extra-pulmonary signs of COVID-19 [ 199 , 200 ].…”