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On the clinical pharmacology of reactive oxygen species

AuthorsCasas, Ana I.; Nogales, Cristian; Mucke, Hermann A. M.; Petraina, Alexandra; Cuadrado, Antonio ; Rojo, Ana I. ; Ghezzi, Pietro; Jaquet, Vincent; Augsburger, Fiona; Dufrasne, Francois; Soubhye, Jalal; Deshwal, Soni; Di Sante, Moises; Kaludercic, Nina; Di Lisa, Fabio; Schmidt, Harald H.H.W.
Issue Date2020
PublisherAmerican Society for Pharmacology and Experimental Therapeutics
CitationPharmacological Reviews 72(4): 801-828 (2020)
AbstractReactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data–enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine.
DescriptionRhian M. Touyz, Associate Editor
Publisher version (URL)https://doi.org/10.1124/pr.120.019422
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