The C-C Chemokine Receptor Type 4 Is an Immunomodulatory Target of Hydroxychloroquine

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.

Keywords: CCR4; COVID-19; SARS-CoV-2; hydroxychloroquine; immunomodulation.

Figure 1

Flowchart summarizing the in silico approach employed to identify the immunomodulatory targets of hydroxychloroquine.

Figure 2

In Silico docking images for hydroxychloroquine and controls against CCR4. (A) Hydrophobicity plot demonstrating hydroxychloroquine interacting with the CCR4 active site. (B) Hydroxychloroquine forms a hydrogen bond with Thr-189 (A) in the CCR4 active site, as depicted in green. (C) Hydrophobicity plots demonstrating AF-399 interacting with the CCR4 active site. (D) AF-399 forms a hydrogen bond with Thr-189 (A) in the CCR4 active site. (E) Hydrophobicity plots demonstrating compound 18a interacting with the CCR4 active site. (F) Compound 18a forms a hydrogen bond with Thr-189 (A) in the CCR4 active site. (G) Hydrophobicity plots demonstrating K777 interacting with the CCR4 active site. (H) K777 forms a hydrogen bond with Thr-189 (A) in the CCR4 active site.