Immune Modulation as a Therapeutic Option During the SARS-CoV-2 Outbreak: The Case for Antimalarial Aminoquinolines

Abstract

The rapid spread, severity, and lack of specific treatment for COVID-19 resulted in hasty drug repurposing. Conceptually, trials of antivirals were well-accepted, but twentieth century antimalarials sparked an impassioned global debate. Notwithstanding, antiviral and immunomodulatory effects of aminoquinolines have been investigated in vitro, in vivo and in clinical trials for more than 30 years. We review the mechanisms of action of (hydroxy)chloroquine on immune cells and networks and discuss promises and pitfalls in the fight against SARS-CoV-2, the agent of the COVID-19 outbreak.

Hydroxychloroquine induces oxidative DNA damage and mutation in mammalian cells

“…The lipophilic and weak basic properties of HCQ enable this chemical to easily pass through the cell membrane and accumulate in acidic intracellular compartments, such as lysosomes [22,23], as well as interact with other molecular targets, such as nucleic acids [19]. HCQ interferes with lysosomal activity and autophagy, disrupts membrane stability, and alters signaling pathways and transcriptional activity, which can lead to inhibition of production of various pro-inflammatory cytokines, and modulation of specific co-stimulatory molecules [19,21,24]. More recently, the utility of HCQ, as an anti-neoplastic drug, has also been demonstrated in various types of cancer [25,26].…”

“…While investigations of the mechanisms of action of HCQ have mainly centered on its intracellular effects, specifically on lysosomal function and activity [19,21,24], very little is known about the interaction of HCQ with DNA, including its DNA damaging-and mutagenic potentials [30]. This is an important gap in knowledge considering that HCQ can produce reactive oxygen species (ROS) [31][32][33][34][35] that are known to cause DNA damage and mutation [36].…”

Hydroxychloroquine pre-exposure prophylaxis to prevent SARS-CoV-2 among health care workers at risk for SARS-CoV-2 exposure: A nonrandomized controlled trial

“…2,[4][5][6][7] Additionally, hydroxychloroquine has immunomodulatory effects that could modify COVID-19 disease by dampening the hyperinflammatory state induced by SARS-CoV-2 infection. 7,8 The U.S. treatment with hydroxychloroquine, either alone or combined with azithromycin, have not demonstrated improvement in clinical outcomes. [9][10][11][12][13][14][15][16][17][18][19] In vitro studies demonstrate that inhibition of SARS-CoV-2 by hydroxychloroquine was greater when the drug was added prior to viral infection compared to post-infection.…”

“…2, 3 Multiple mechanisms for the inhibition of SARS-CoV-2 by hydroxychloroquine have been proposed, including impairment of spike protein binding to cellular gangliosides, blockade of virus transport from early endosomes to lysosomes, and increased intraorganellar pH. 2, 4-7 Additionally, hydroxychloroquine has immunomodulatory effects that could modify COVID-19 disease by dampening the hyperinflammatory state induced by SARS-CoV-2 infection. 7, 8 The U.S. Food and Drug administration issued an emergency use authorization (EUA) for hydroxychloroquine on 28 March 2020, but revoked the EUA on 15 June 2020 based on lack of clinical benefit during treatment of patients hospitalized with COVID-19.…”

“…2, 4-7 Additionally, hydroxychloroquine has immunomodulatory effects that could modify COVID-19 disease by dampening the hyperinflammatory state induced by SARS-CoV-2 infection. 7, 8 The U.S. Food and Drug administration issued an emergency use authorization (EUA) for hydroxychloroquine on 28 March 2020, but revoked the EUA on 15 June 2020 based on lack of clinical benefit during treatment of patients hospitalized with COVID-19. The majority of studies of COVID-19 treatment with hydroxychloroquine, either alone or combined with azithromycin, have not demonstrated improvement in clinical outcomes.…”