Abstract
The emergence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) in China, reported to the World Health Organization on December 31, 2019, has led to a large global pandemic and is a major public health issue. As a result, there are more than 200 clinical trials of COVID-19 treatments or vaccines that are either ongoing or recruiting patients. One potential therapy that has garnered international attention is hydroxychloroquine; a potent immunomodulatory agent FDA-approved for the treatment of numerous inflammatory and autoimmune conditions, including malaria, lupus, and rheumatoid arthritis. Hydroxychloroquine has demonstrated promise in vitro and is currently under investigation in clinical trials for the treatment of COVID-19. Despite an abundance of empirical data, the mechanism(s) involved in the immunomodulatory activity of hydroxychloroquine have not been characterized. Using the unbiased chemical similarity ensemble approach (SEA), we identified C-C chemokine receptor type 4 (CCR4) as an immunomodulatory target of hydroxychloroquine. The crystal structure of CCR4 was selected for molecular docking studies using the SwissDock modeling software. In silico, hydroxychloroquine interacts with Thr-189 within the CCR4 active site, presumably blocking endogenous ligand binding. However, the CCR4 antagonists compound 18a and K777 outperformed hydroxychloroquine in silico, demonstrating energetically favorable binding characteristics. Hydroxychloroquine may subject COVID-19 patients to QT-prolongation, increasing the risk of sudden cardiac death. The FDA-approved CCR4 antagonist mogalizumab is not known to increase the risk of QT prolongation and may serve as a viable alternative to hydroxychloroquine. Results from this report introduce additional FDA-approved drugs that warrant investigation for therapeutic use in the treatment of COVID-19.
Highlights
The novel coronavirus SARS-CoV-2 (SARS-CoV-2; COVID-19) has emerged as an international outbreak of acute respiratory illness
Results from a clinical trial hosted at Renmin Hospital of Wuhan University indicated that hydroxychloroquine treatment led to a reduction in time to clinical recovery (TTCR); reduced the body temperature recovery time, and shortened the duration of pneumonia relative to control subjects
Four hits with significant p-values were discovered: Histidine-rich protein PFHRP-II (p = 1.63E-143), histamine N-methyltransferase (p=3.96E-53), DNA gyrase subunit B (3.08E-37), and C-C chemokine receptor type 4 (CCR4) (p = 3.79E-27)
Summary
The novel coronavirus SARS-CoV-2 (SARS-CoV-2; COVID-19) has emerged as an international outbreak of acute respiratory illness. The first case of COVID-19 was reported to the World Health Organization on December 31, 2019, news reports have described the outbreak initiating as early as November 17, 2019 (Ma, 2020; Scher, 2020; Walker, 2020). Hydroxychloroquine has demonstrated promise in vitro and is currently being investigated in clinical trials for use as pre-exposure or post-exposure prophylaxis of COVID-19 infection, as well as in the treatment of patients with an active COVID-19 infection (World Health Organization, 2020). Despite promising data in Europe and China, ongoing clinical trials in the United States have not yet demonstrated that hydroxychloroquine is safe and effective in the treatment of patients with COVID-19 (Food and Drug Administration, 2020)
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