Polymorphisms such as p.Met383Thr, p.Pro389His, and p.Asp427Tyr slightly inhibit interaction between ACE2 and SARS-CoV-2 S protein.  This observation may contribute to why hydroxychloroquine was not found to be statistically significant in decreasing mortality rates in hospitalized COVID-19 patients.  

ACE2 Variation May Influence the Efficacy of Hydroxychloroquine or Chloroquine in Treating COVID-19

Hydrochloroquine function by increasing pH intracelluarly, affecting the function of hydrolases and the assembly of macromolecules in endosomes. The antimalarial prevents the formation of peptide MHC complexes which stimulate an immunologic response.

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University of California, Santa Cruz

Michigan State University

The biochemical interaction through which a drug produces its pharmaceutical effect. This generally involves enzymes, receptors, and other targets of cells to produce a cellular response.

Mechanism of Action

- Findings in support of using HCQ for COVID-19 treatment
- Findings opposed to use of HCQ for COVID-19 treatment 
- HCQ Mechanism of action
- Toxicities of HCQ

Findings Related to the Use of Hydroxychloroquine (HCQ) as treatment for COVID-19

Fox, R. I. (1993). Mechanism of action of hydroxychloroquine as an antirheumatic drug. Seminars in Arthritis and Rheumatism, 23(2), 82-91. doi:10.1016/s0049-0172(10)80012-5

Mechanism of action of hydroxychloroquine as an antirheumatic drug

Computerized molecular docking assays were conducted to assess the roles of hydroxychloroquine (HCQ) and chloroquine (CQ) in preventative or therapeutic care of COVID-19.  Studies analyzed these drug interactions with SARS-CoV-2 proteins, ACE2, TMPRSS2, and other protein targets.  HCQ and CQ were not found to strongly interact with viral proteins, including its RNA polymerase, main protease, or ligand.  However, five possible binding sites were discovered on the ACE2 receptor.  

Using Molecular Docking to Determine the Mechanism of Action of Hydroxychloroquine/Chloroquine on SARS-CoV-2

- Hazard ratio for  in-hospital mortality amongst hospitalized patients in NYC were not significantly different for those given HCQ

- Odds of cardiac arrest were higher in hospitalized patients in NYC given HCQ

- Odds of abnormal ECG findings were higher in hospitalized patients in NYC given HCQ

- From multinational registry of patients hospitalized between 12/20/19 and 4/14/20, individuals treated with HCQ had a higher risk of in-hospital mortality compared to an untreated control group

-  From multinational registry of patients hospitalized between 12/20/19 and 4/14/20, individuals treated with HCQ had a higher risk of clinically significant ventricular arrhythmia compared to an untreated control group

-  Hydroxychloroquine did not substantially reduce symptom severity in patients with early or mild COVID-19.
 
-  As of now no randomized clinical trials reported have shown a positive correlation to COVID-19 recovery through the use of hydroxychloroquine

- A small randomized trial in Shanghai, China by Chen J, Liu D, Liu L, et al. revealed that by day 7, a total of 86% of the patients in the HCQ-treated group and 93% of those in the control group had negative results on viral throat swabs

- Researchers who used a randomized, double-blind, placebo-controlled study found no significant difference between new illness and symptoms compatible with COVID-19 infection in the hydroxychloroquine sulfate and placebo groups (11.8% and 14.3%, respectively).

- A study including 176 hospitals in the UK showed no significant difference between COVID-19 patients who received hydroxychloroquine and those who received usual care alone.

Findings opposed to use of Hydroxychloroquine (HCQ) as COVID-19 intervention

- In a French open-label non-randomized clinical trial, more patients treated with HCQ tested negative for COVID-19 by  day 6 after inclusion in study

- In a Chinese small randomized clinical trial, researchers reported a faster mean time to clinical recovery in the experimental group treated with HCQ than in the control group

- In a French uncontrolled, non-comparative, observational study, a significant decline of nasopharyngeal viral load and viral carriage duration was noted in patients treated with both HCQ and azithromycin (azm) 

Findings in favor of treating COVID-19 infections with hydroxychloroquine

- Toxicities are similar to chloroquine but are not as common 

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