A review on possible modes of action of chloroquine/hydroxychloroquine: repurposing against SAR-CoV-2 (COVID-19) pandemic

Abstract

Chloroquine (CQ) and its analogue hydroxychloroquine (HCQ) have long been used worldwide as frontline drugs for the treatment and prophylaxis of human malaria. Since the first reported cases in Wuhan, China, in late December 2019, humans have been under threat from coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2 (previously known as 2019-nCoV), subsequently declared a pandemic. While the world is searching for expedited approval for a vaccine, which may be only preventative and not a cure, physicians and country leaders are considering several concerted clinical trials suggesting that the age-old antimalarial drugs CQ/HCQ could be a potent therapeutic against COVID-19. Based on accumulating scientific reports, here we highlight the possible modes of action of CQ/HCQ that could justify its use against viral infections. Considering the global health crisis of the COVID-19 pandemic, the option of repurposing old drugs, e.g. CQ/HCQ, particularly HCQ, for the treatment of SARS-CoV-2 infection could be a good choice. CQ/HCQ has diverse modes of action, including alteration of the acidic environment inside lysosomes and late endosomes, preventing endocytosis, exosome release and phagolysosomal fusion, and inhibition of the host cytokine storm. One or more diverse mechanisms might work against viral infections and reduce mortality. As there is no cure for COVID-19, clinical testing of HCQ is urgently required to determine its potency against SARS-CoV-2, as this is the currently available treatment option. There remains a need to find other innovative drug candidates as possible candidates to enter clinical evaluation and testing.

Keywords: COVID-19; Chloroquine; Hydroxychloroquine; Pandemic; SARS-CoV-2.

Fig. 1

Development of chloroquine and its analogues.

Fig. 2

Schematic diagram of the role of chloroquine (CQ) and hydroxychloroquine (HCQ) in the intracellular space. The drugs increase the pH of endosomes and lysosomes. As a result, activation of T-cells and other cytokines is repressed.

Fig. 3

Chloroquine (CQ) and hydroxychloroquine (HCQ) suppress DNA sensing by the cGAS-STING pathway and Toll-like receptor (TLR) signalling.

Fig. 4

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry occurs via the angiotensin-converting enzyme 2 (ACE2), the sialic acid receptor, the transmembrane serine protease 2 (TMPRSS2) and CD147. The viral spike protein binds to receptor(s) present on the cell surface of host cells and enters the cell. CQ, chloroquine.