Pharmacological Modulators of Autophagy as a Potential Strategy for the Treatment of COVID-19

Abstract

The family of coronaviruses (CoVs) uses the autophagy machinery of host cells to promote their growth and replication; thus, this process stands out as a potential target to combat COVID-19. Considering the different roles of autophagy during viral infection, including SARS-CoV-2 infection, in this review, we discuss several clinically used drugs that have effects at different stages of autophagy. Among them, we mention (1) lysosomotropic agents, which can prevent CoVs infection by alkalinizing the acid pH in the endolysosomal system, such as chloroquine and hydroxychloroquine, azithromycin, artemisinins, two-pore channel modulators and imatinib; (2) protease inhibitors that can inhibit the proteolytic cleavage of the spike CoVs protein, which is necessary for viral entry into host cells, such as camostat mesylate, lopinavir, umifenovir and teicoplanin and (3) modulators of PI3K/AKT/mTOR signaling pathways, such as rapamycin, heparin, glucocorticoids, angiotensin-converting enzyme inhibitors (IECAs) and cannabidiol. Thus, this review aims to highlight and discuss autophagy-related drugs for COVID-19, from in vitro to in vivo studies. We identified specific compounds that may modulate autophagy and exhibit antiviral properties. We hope that research initiatives and efforts will identify novel or “off-label” drugs that can be used to effectively treat patients infected with SARS-CoV-2, reducing the risk of mortality.

Wheat Germ Spermidine and Clove Eugenol in Combination Stimulate Autophagy In Vitro Showing Potential in Supporting the Immune System against Viral Infections

“…Autophagy is also involved in the specific disposal of intercellular viral pathogens (virophagy), resulting in the restriction of viral replication and the subsequent containment of infection [ 4 , 5 , 6 ]. However, several viral pathogens, including the Betacoronavirus genus (β-CoVs) with single-stranded positive sense RNA genomes, “hijack” autophagy machinery to foster replication and avoid degradation [ 4 , 7 , 8 ]. More specifically, very recent studies, forming the subject of current reviews [ 4 , 6 , 7 , 8 , 9 , 10 ], have implicated autophagy in severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) replication and pathogenesis.…”

Clinical-Epidemiology Aspect of Inpatients With Moderate or Severe COVID-19 in a Brazilian Macroregion: Disease and Countermeasures

“…The use of antifungals, antimalarials, and other drugs that inhibit autophagy, such as rapamycin, chloroquine and hydroxychloroquine, cannabidiol, and azithromycin, were tested at the beginning of the pandemic ( Morris et al., 2020 ; Pereira et al., 2021 ) and have proven to be one of the least efficient strategies. Laboratory and patient data thus far do not support their use in the affected population.…”

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

“…PRAS40 blocks binding of p70 ribosomal S6 kinase (p70S6K) and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) to Raptor that can affect mTORC1 activity [165,166]. Rapamycin mTORC1 [24] as well inhibits activation of mTORC1 [162,[167][168][169][170]. mTORC2 has some different components when compared to mTORC1 [171].…”