Azithromycin and ciprofloxacin have a chloroquine-like effect on respiratory epithelial cells

Vojo Deretic; Graham S Timmins

In conclusion, the relationships demonstrated in this study indicate that a set of FDA-approved drugs, CQ, AZT, CPX, with known safety profiles, act by controlling pH of intracellular organelles in respiratory epithelial cells, a highly relevant target for CoV2. Furthermore, our previous studies of phosphodiesterase 5 inhibitiors show similar effects, and these may also be further tested. 30 The alterations of pH in organelles of the secretory pathway, especially TGN 31 , may alter glycosylation of both the receptors for CoV2, such as ACE2, which binds the spike protein, and glycosylation of CoV2 proteins during their biogenesis and assembly. Importantly, coronavirus M proteins govern viral budding at the ERto-Golgi intermediate compartment but penetrate deeper into the Golgi apparatus 54 , and among the pathogenic CoVs, at least the MERS CoV M protein possesses TGN localization signals 55 . The effects of chloroquine have been observed with other viruses including HIV gp120 glycosylation defect and loss of infectivity 56, 57 as well as HSV arrest of noninfectious parties in the TGN 58 . Our studies here show that CF respiratory epithelial cell normalization is based on a neutralization of the pre-existing pathologically hyperacidified compartments due to the underlying CF disease, resulting in normalization of glycosylation in CF respiratory epithelial cells. We postulate here that the acidotropic and neutralization effects of AZT, CPX and CQ in normal cells would result in vectorially similar pH shifts away from optimal for the function of enzymes within the secretory pathway that would also alter glycosylation.