Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery. 2020;6(1). doi:10.1038/s41421-020-0156-0

Review written by:

Robert Parry, edited by Shawn Sun

Yellow - Reasonably well-designed study utilizing a common in vitro model for viral infection, demonstrating an inhibitory effect of HCQ on SARS-CoV-2 infection in this model. Suggests utility for further clinical trials of hydroxychloroquine (HCQ). Does not, in itself, support the clinical use of HCQ for SARS-CoV-2 infection.

Chloroquine (CQ) has the potential to be an effective treatment for SARS-CoV-2, and hydroxychloroquine (HCQ), a derivative believed to be less toxic, may also be an option.  The authors cite a previous animal study where HCQ was shown to be less toxic than CQ (~40%) (1). However, their in vitro experiments in a green monkey kidney cell line (the model for all experiments) show a similar 50% cytotoxic concentration (CC50) between HCQ and CQ.

Inhibition of SARS-CoV2 virion production 48 hours after infection at various multiplicities of infection (MOI) was measured by viral RNA copy # in culture supernatant. CQ had a lower EC50 (concentration at 50% maximal effectiveness) ranging from 0.59x to 0.94x compared to that of HCQ, depending on the MOI. This resulted in CQ having a higher selectivity index (SI = CC50/EC50) by 1.17x to 2.66x compared to HCQ, depending on the MOI.

Mechanistically, both CQ and HCQ were shown to reduce the transport of SARS-CoV-2 from early endosomes (EE) to endolysosomes (EL), which is believed to be a requirement to release the virion. Ninety minutes post infection in untreated cells, 16.2% of SARS-CoV-2 virions were in early endosomes (EEs) and 34.3% in endolysosomes (ELs). Both CQ and HCQ increased the proportion of virions in EEs (35.3% and 29.2%) and reduced the proportion in ELs (2.4% and 0.03%). It was qualitatively observed that both CQ and HCQ greatly increased EE size. HCQ but not CQ greatly increased EL size and number (qualitatively). Taken together, the drugs reduced progression of virions from EEs to ELs, which may disrupt release of viral genome.

Overall, hydroxychloroquine and chloroquine showed similar levels of cytotoxicity in this study. Both agents reduced viral production in a green monkey kidney cell line, however, chloroquine was modestly more potent at a variety of MOI’s than HCQ.

Review Notes

In vitro study that awaits further clinical trials before conclusions can be made for the efficacy of hydroxychloroquine or chloroquine in treating SARS-CoV-2 infection in humans.

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