Oxygen demand triggers cell changes in gene expression driven by Hypoxia Inducible Factors proteins (HIF) the biology of which has been extensively revised elsewhere. The biology of HIF (HIFa isoforms) has expanded in the last decade from their role in angiogenesis and cancer to their prevalent position in the context of pathological processes of metabolic rewiring that modulates immunity during the process of infection diseases. HIF are obligated heterodimers consisting of an oxygen-regulated a subunit (1,2,3α) and a constitutively expressed b subunit, also known as aryl hydrocarbon receptor nuclear translocator (ARNT).
The relevance of HIFa proteins resides in the pivotal role played by their target genes in the cell metabolism and energy balance (e.g., NOS2, CAIX, PHD3, GLUT1, GLUT4, GAPDH, PGK1, trasferrin, etc.), HIFa proteins exert the control of key pathways that are essential for cell physiology, in part by reprogramming cellular metabolism guiding the shift to glucose catabolism by promoting the expression of glucose tansporters, glycolytic enzymes, and LDHA, which replenishes NAD+ for further glycolysis, with obvious implications in physiopathological events including infection of a wide variety of microbes. It is nowadays well-accepted that up to 75% of known drugs may have new therapeutic uses. Each drug in clinical application for some years has about 20 different uses outside of its indication (“off-label”), two thirds of which are initiated by prescribing physicians. Therefore, a selection of HIFα modulators from would be a limited but rational-oriented screening effort against coronavirus and Leishmania, using the macrophage infection model assay. To further exemplify this last but not limited to, some drugs with different mechanism are described in the literature for intervening HIF pathway, including mRNA expression (aminoflavones), HIF protein synthesis (cardiac glycosides, rapamycin, topotecan, CPTs), HIF-stabilization (tricostatin, cyclosporine, YC-1), HIF dimerization (acriflavin), HIF/ DNA binding (echinomycin, doxorubicin, anrhracyclines), HIF transcriptional activity (chetomin) or at multiple levels of signal transduction (metformin, losartan, acetylcysteine).