Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases

Abstract

Emerging viruses such as HIV, dengue, influenza A, SARS coronavirus, Ebola, and other viruses pose a significant threat to human health. Majority of these viruses are responsible for the outbreaks of pathogenic lethal infections. To date, there are no effective therapeutic strategies available for the prophylaxis and treatment of these infections. Chloroquine analogs have been used for decades as the primary and most successful drugs against malaria. Concomitant with the emergence of chloroquine‐resistant Plasmodium strains and a subsequent decrease in the use as antimalarial drugs, other applications of the analogs have been investigated. Since the analogs have interesting biochemical properties, these drugs are found to be effective against a wide variety of viral infections. As antiviral action, the analogs have been shown to inhibit acidification of endosome during the events of replication and infection. Moreover, immunomodulatory effects of analogs have been beneficial to patients with severe inflammatory complications of several viral diseases. Interestingly, one of the successful targeting strategies is the inhibition of HIV replication by the analogs in vitro which are being tested in several clinical trials. This review focuses on the potentialities of chloroquine analogs for the treatment of endosomal low pH dependent emerging viral diseases.

The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19

“…Although most of the evidence in this field regards CQ, there are some data showing similar effects by HCQ. Additionally, current data support that the mechanism of action of the two molecules is equivalent and HCQ appears to be significantly less toxic and has almost completely replaced the use of CQ in the treatment of rheumatic diseases [77,78].…”

“…However, the circulating unprotonated portion can easily cross cell membranes and, due to its basic charge, tends to accumulate in acidic organelles such as lysosomes, Golgi vesicles and endosomes, where it binds to free protons, thus significantly increasing the pH. Thus, a large number of enzymes contained in these organelles, which optimally work in the acidic milieu, are inhibited [76,77]. This mechanism is presumably at the basis of the direct anti-parasitic, anti-viral, and immunomodulatory effects of the molecule.…”

The A–Z of Zika drug discovery

“…The antimalarial drug chloroquine is known to exhibit broadspectrum antiviral activity [158]. It is a weak base (pK 1 = 8.1, pK 2 = 10.1), and the pH of lysosomes in the presence of chloro-quine increases from $4 to $6 [159].…”

Novel activities of safe-in-human broad-spectrum antiviral agents

“…For example, lipid-lowering statins (atorvastatin, lovastatin, simvastatin, and fluvastatin) inhibit cellular HMG-CoA reductase and attenuate replication of some enveloped viruses (Bernal et al, 2017;Enserink, 2005). Anti-malaria quinolones (chloroquine and hydroxychloroquine) inhibit acidification of endosomes, which is an essential process for uncoating of ssRNA viruses (Al-Bari, 2017). Anticancer kinase inhibitors dasatinib, imatinib, gefitinib, nilotinib, erlotinib and sunitinib impair intracellular viral trafficking and exert BSA effects (Bekerman et al, 2017;Schor and Einav, 2018).…”