Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by massive
inflammation of the arterial endothelium accompanied by vasoconstriction and widespread pulmonary micro thrombi. As a result, due to the destruction of
nitric oxide (•NO) by inflammatory
superoxide (O2•-), pulmonary •NO concentration ceases, resulting in uncontrolled platelet aggregation and massive
thrombosis, which kills the patients. Introducing •NO by inhalation (INO) may replace the loss of endothelium-derived •NO. The first results from clinical trials with INO in SARS-CoV-2 patients show a rapid and sustained improvement in cardiopulmonary function and decreased
inflammation. An ongoing phase III study is expected to confirm the method's efficacy. INO may hence become a first line treatment in SARS-CoV-2 patients. However, due to the rapid inactivation of •NO by
deoxyhemoglobin to
nitrate, pulmonary administration of •NO will not protect remote organs. Another INO-related pharmacological approach to protect SARS-CoV-2 patients from developing life-threatening disease is to inhibit the O2•--driven destruction of •NO by neutralizing inflammatory O2•-. By making use of low molecular weight compounds that mimic the action of the
enzyme manganese superoxide dismutase (MnSOD). The MnSOD mimetics of the so-called
porphyrin type (e.g.,
AEOL 10150),
salen type (e.g., EUK-8) and cyclic
polyamine type (e.g., M40419, today known as
GC4419 and
avasopasem manganese) have all been shown to positively affect the inflammatory response in lung epithelial cells in preclinical models of
chronic obstructive pulmonary disease. The
Manganese diPyridoxyL EthylDiamine (
MnPLED)-type
mangafodipir (
manganese dipyridoxyl diphosphate-MnDPDP), a magnetic resonance imaging (MRI)
contrast agent that possesses MnSOD mimetic activity, has shown promising results in various forms of
inflammation, in preclinical as well as clinical settings. Intravenously administration of
mangafodipir will, in contrast to INO, reach remote organs and may hence become an important supplement to INO. From the authors' viewpoint, it appears logical to test mangafodipr in
COVID-19 patients at risk of developing life-threatening SARS-CoV-2. Five days after submission of the current manuscript, Galera
Pharmaceuticals Inc. announced the dosing of the first patient in a randomized, double-blind pilot phase II clinical trial with
GC4419 for
COVID-19. The study was first posted on ClinicalTrials.gov (Identifier: NCT04555096) 18 September 2020.