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

Vojo Deretic; Graham S Timmins

The alterations of pH in organelles of the endosomal pathway may have effects on host proteases acting upon the CoV2 Spike protein to execute its cleavage necessary for virus entry. The inhibition of viral entry in recent cellular systems is best achieved with a combination of camostat mesylate (an inhibitor of TMPRSS2 protease) plus E-64d, an inhibitor of lysosomal cathepsins 59 . It has been noted that CoV2, unlike SARS-CoV, possesses a novel furin cleavage site within its Spike protein 60 . Our studies here show that AZT can reduce furin activity that is abundantly present in respiratory epithelial cells. Multiple proteases are proposed to cleave CoV2 Spike, including TMPRSS2 59 (which also acts on SARS-CoV 61-63 ), furin 60 , and lysosomal hydrolases 59 . This warrants consideration of a more general approach to their inhibition, such as altering pH, rather than focusing solely on a specific host protease. We propose that the drugs studied here, CQ, AZT and CPX, may modulate these aspects of host-pathogen interactions and virus infectious cycle, with immediate compassionate use in the clinic or in controlled clinical trials. A validation of the effects of CPX in COVID-19 patients would enable the utilization of this drug to alleviate likely shortages in HCQ and AZT. CPX is a part of the US Health and Human Services Strategic National Stockpile 64 , which can be mobilized during regional or national emergencies.