Currently, an efficient treatment for COVID-19 is still unavailable, and people are continuing to die from complications associated with SARS-CoV-2 infection. Thus, the development of new therapeutic approaches is urgently needed, and one alternative is to target the mechanisms of autophagy. Due to its multifaceted role in physiological processes, many questions remain unanswered about the possible advantages of inhibiting or activating autophagy. Based on a search of the literature in this field, a novel analysis has been made to highlight the relation between the mechanisms of autophagy in antiviral and inflammatory activity in contrast with those of the pathogenesis of COVID-19. The present analysis reveals a remarkable coincidence between the uncontrolled inflammation triggered by SARS-CoV-2 and autophagy defects. Particularly, there is conclusive evidence about the substantial contribution of two concomitant factors to the development of severe COVID-19: a delayed or absent type I and III interferon (IFN-I and IFN-III) response together with robust cytokine and chemokine production. In addition, a negative interplay exists between autophagy and an IFN-I response. According to previous studies, the clinical decision to inhibit or activate autophagy should depend on the underlying context of the pathological timeline of COVID-19. Several treatment options are herein discussed as a guide for future research on this topic.
Although further research is needed on the intricate relation between viral infections and autophagy, the information encountered in the literature justifies the plausible therapeutic efficacy of inhibiting or activating this cellular mechanism. The current focus is on a limited number of inhibitors and activators of autophagy, given the strategy of targeting the antiviral response to diminish viral replication in the first phase of COVID-19, and the exaggerated inflammation to avoid complications in the third phase of the disease. It is important to consider the wide range of autophagic activity to avoid negative consequences. Numerous compounds are being investigated nowadays as up- or downregulators of autophagy. Some authors have provided a comprehensive summary of autophagy-related drugs or compounds as novel treatments against SARS-CoV-2 here are several autophagy inhibitors with promise for a positive intervention in the pathogenesis of anti-SARS-CoV-2. For instance, the first drugs suggested for the treatment of COVID-19 were chloroquine (CQ) and its less toxic derivative, hydroxychloroquine (HCQ) , which are known to inhibit autophagic flux by interfering with autophagosome–lysosome fusion, increasing the endosomal/lysosomal pH. Due the broad-spectrum antiviral effects of CQ and HCQ, their applications have been proposed against HIV, SARS-CoV and Zika. In vitro, HCQ is effective for inhibiting the entry step, as well as the post-entry stages of SARS-CoV-2, in Vero E6 cells. This effect is due to changing the glycosylation of ACE2 receptor and spike protein, in addition to the failure of the transport of virions to the releasing site by blocking endosomal maturation. Some limited clinical trials were conducted in cohorts of patients with COVID-19 which have suggested the efficacy of CQ and HCQ to mitigate SARS-CoV-2-induced pneumonia and decrease the mortality rate. Contrarily, other clinical studies do not find clinical benefits of HCQ for COVID-19. The discrepancy between studies probably reflects differences in patients enrolled, design of the studies, dosages and timeline of pathogenesis of COVID-19. This asseveration is supported by some studies which have showed some benefits of HCQ in early and mild COVID-19, mainly associated with viral load reduction.
HCQ and CQ can inhibit certain cellular functions and molecular pathways involved in immune activation. For instance, HCQ and CQ interfere with TLR and STING signaling, which prevents the production of pro-inflammatory cytokines, including IFN response. The various modes of action of these drugs make their use in therapeutic interventions for COVID-19 difficult. It is likely that their applications are dependent on the inflammatory conditions of the disease. Although severe adverse effects led to the suspension of clinical trials and their therapeutic use to treat COVID-19, more in vitro studies and clinical trials are needed to understand the direct and indirect action mechanisms of these drugs to improve the CQ and HCQ-based COVID-19 treatments
Lysosomotropic compounds ARN5187 and Lys05 are also good candidates for a clinical trial to evaluate their antiviral activity against SARS-CoV-2. They block the final maturation of autolysosomes and thus inhibit autophagy. Eugenol and evodiamine are other autophagy inhibitors with promise for treating COVID-19, given the evidence of their antiviral properties against the influenza A virus. Whereas the former interferes with autophagy by avoiding the dissociation of Beclin1-Bcl2, the latter inhibits the formation of the Atg5-Atg12/Atg16 heterotrimer.
Other plausible therapeutic alternatives are inhibitors of the ULK complex or PI3-K in order to disable autophagy. Accordingly, inhibitors of the ULK complex that suppress autophagy and the autophagic flux are ULK-100, ULK-101, compound 6, MRT67307, MRT68921 and SBI-0206965. Among the inhibitors of PI3K commonly employed to block autophagy are 3-methyladenine, wortmannin, LY294002, PT210 and GSK-2126458. Inhibitors of VPS34 (a PI3K) are VPS34-IN1 and VVPS34-IN1, which have antiviral properties against SARS-CoV-2. The analogues of these inhibitors should also be investigated: Spautin-1, SAR405, compound 31 and PIK-III.
In the third and critical stage of COVID-19 (characterized by an uncontrolled inflammatory response), it may be advantageous to administer activators of autophagy. Some drugs approved by the FDA for the treatment of other diseases act as autophagy inducers, although their mechanisms and their capacity for promoting autophagy are not yet clear. For instance, metformin is an oral anti-diabetic drug frequently prescribed to suppress glucose production in the liver. It has also been assessed for its anticancer effect. A recent review has mentioned the positive impact of metformin on the prognosis of hospitalized patients with diabetes type 2 and COVID-19. The author did not point to autophagy as the means of restoring homeostasis, but this drug is a known promotor of autophagy through the activation of AMPK and regulation of mTOR, mechanisms related to its anti-inflammatory effect.
Vitamin D3, a pleiotropic hormone with activity against intracellular Mycobacterium tuberculosis, has the capacity to evoke autophagy. Some studies have found that vitamin D3 supplementation reversed a strong inflammatory response. However, it must be studied more rigorously in relation to the activation of autophagy before considering randomized clinical trials on its efficacy for treating COVID-19. Spermidine, a natural polyamine, has been correlated with the control of cytomegalovirus infection. It restores homeostasis in deregulated autophagy and reestablishes CD8 (+) T cell memory formation by an autophagy-dependent process capable of improving immunity. Resveratrol has well-recognized antiviral and anti-inflammatory activity, and the latter seems to be related to autophagy in endothelial cells. The therapeutic potential of resveratrol against emerging respiratory viruses has been discussed. For cytomegalovirus infection, trehalose (an activator of autophagy) has been suggested as a therapeutic antiviral approach and proposed as a potential preventative treatment for SARS-CoV-2 infection.
Additionally, there are other drugs with potential antiviral efficiency against SARS-CoV-2 in evaluation. Nitazoxanide is a commercial antiprotozoal agent with antiviral potential against a broad range of viruses including MERS-CoV and other coronaviruses. Nitazoxanide induces autophagy and inhibits the intracellular proliferation of M. tuberculosis. Ivermectin, a drug known as a specific inhibitor of nuclear import mediated by Importin alpha/beta and an in vitro inhibitor of SARS-CoV-2 replication, has been reported as an inductor of autophagy through the AKT/mTOR signaling pathway. Emtricitabine and Tenofovir have shown moderate reduction of the overall clinical scores of SARS-CoV-2 infected ferrets; these drugs modulate autophagy through the increased expression and accumulation of SQSTM1/p62 and block the autolysosomes’ formation, respectively. For these drugs, several action modes have been described, and further in vitro studies and clinical trials are needed to establish if their antiviral properties are due to their influence over autophagy.
In addition to pharmacological agents to modulate autophagy, the use of light against COVID-19 is in an exploratory stage, predominantly photothermal and ablation techniques applied in critical cases to avoid catastrophic effects. These ultrashort laser pulses may provoke sharp and selective photodamage at specific subcellular sites and thus trigger signaling pathways. Photo-induced regulation of transcription factors eventually gives rise to autophagy. The production of ROS resulting from photothermal activity was correlated with the downregulation of the Akt-mTOR-p70S6K pathway, which turns on autophagy.
Although laser therapy for coronavirus is still in its infancy, it represents an opportunity to precisely stimulate cell processes involved in the regulation of the immune response (e.g., autophagy). Theoretical calculations and practical experimentation alike will be required to develop this technology.
Despite the promising therapeutic strategy of targeting autophagy to treat COVID-19, especially in the first and the third stages of the disease, further research is mandatory to define the advantages and disadvantages in regard to efficacy and safety. The ectopic modulation of autophagy represents an approach of remarkable clinical significance. Drugs targeting autophagy may be employed to counteract the evolutionary strategies developed by several viruses to harness the autophagy machinery in their replication and propagation process. Moreover, the modulation of autophagy also provides a potential treatment in the current condition for COVID-19, where there are no antiviral specific drugs. Since autophagy is a central modulator of innate and adaptative immunity, its modulation can provide an effective solution avoiding the exacerbated immune response and improving the morbidity and mortality rates in patients with severe COVID-19. Moreover, the autophagy-activated drugs offer the ability to restore homeostasis in diseases associated with dysfunctional autophagy to balance the antiviral and inflammatory response. In either situation, the decision to inhibit or activate the autophagy seems to depend on various factors, such as age, nutritional health conditions, genetic and the pre-existence of diseases associated with autophagy defects. Furthermore, since autophagy has a fundamental role in a plethora of signaling pathways, future studies seem to be essential to clarify its impact on the activation/deactivation of several cell mechanisms.
The complexity of the cellular and multiorgan disorders caused by SARS-CoV-2 requires novel and sophisticated therapeutic approaches. One possibility is to target autophagy, which could be responsible for the ineffective immune response that is unable to control viral replication and therefore ends up promoting spiraling inflammation. In light of the literature considered here, it is plausible to propose the inhibition of autophagy in the first stage of COVID-19 to prevent SARS-CoV-2 from taking advantage of this process to replicate itself. Moreover, since autophagy acts as a negative regulator of IFN response, its inhibition might restore the antiviral efficiency of the immune response to control the viral replication. On the other hand, uncontrolled inflammation is the hallmark of COVID-19 in its third and most severe stage. As it has been highlighted in the current review, autophagy participates in diverse signaling pathways in the antiviral immune response, including many involved in inflammation. Moreover, the comorbidities associated with severe COVID-19 have been related to dysfunctional autophagy. Therefore, activation of autophagy in this critical stage represents a potential approach to regulate the exacerbated immune response and restore homeostasis. Thus, the modulation of autophagy to restore homeostasis in the immune response to COVID-19 represents an important challenge, implying the ability to improve the antiviral response, limit inflammation and avoid provoking other complications. To date, pharmaceutical intervention in the antiviral and anti-inflammatory pathways of autophagy during the pathogenesis of COVID-19 has not received adequate attention as a clinical target, in spite of the fact that it plays a fascinating and vital role in governing the viral mechanisms capable of sequestering the host immune processes. Even though targeting autophagy could be an efficient strategy for treating COVID-19, it is essential to acquire an in-depth understanding of the interplay between the pathological characteristics of the disease and the host mechanisms of autophagy that participate in the control of viral replication and regulation of the inflammatory response. Future studies are needed to improve knowledge of such mechanisms, as well as clinical trials to test drugs that target autophagy through mono- or combination therapy with autophagic inhibitors or activators of specific pathways
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