Updated Approaches against SARS-CoV-2

Li, Haiou; Zhou, Yunjiao; Zhang, Meng; Wang, Haizhou; Zhao, Qiu; Liu, Jing

doi:10.1128/aac.00483-20

Cited by 230 publications

(232 citation statements)

References 47 publications

(46 reference statements)

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“…[10,[26][27][28] Many potential therapies have been proposed with a subset currently undergoing investigation. [29,30] Meanwhile, extensive efforts to date have been appropriately focused on screening, identification, and containment through the collaboration and coordination between global and local health and governmental agencies. [31] Unfortunately, these public health efforts have had, at best, mixed success curbing the spread of the pandemic.…”

Section: Introductionmentioning

confidence: 99%

Understanding the renin–angiotensin–aldosterone–SARS-CoV axis: a comprehensive review

et al. 2020

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ImportanceCoronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic with significant morbidity and mortality since first appearing in Wuhan, China, in late 2019. As many countries are grappling with the onset of their epidemics, pharmacotherapeutics remain lacking. The window of opportunity to mitigate downstream morbidity and mortality is narrow but remains open. The renin–angiotensin–aldosterone system (RAAS) is crucial to the homeostasis of both the cardiovascular and respiratory systems. Importantly, SARS-CoV-2 utilises and interrupts this pathway directly, which could be described as the renin–angiotensin–aldosterone–SARS-CoV (RAAS–SCoV) axis. There exists significant controversy and confusion surrounding how anti-hypertensive agents might function along this pathway. This review explores the current state of knowledge regarding the RAAS–SCoV axis (informed by prior studies of SARS-CoV), how this relates to our currently evolving pandemic, and how these insights might guide our next steps in an evidence-based manner.ObservationsThis review discusses the role of the RAAS–SCoV axis in acute lung injury and the effects, risks and benefits of pharmacological modification of this axis. There may be an opportunity to leverage the different aspects of RAAS inhibitors to mitigate indirect viral-induced lung injury. Concerns have been raised that such modulation might exacerbate the disease. While relevant preclinical, experimental models to date favour a protective effect of RAAS–SCoV axis inhibition on both lung injury and survival, clinical data related to the role of RAAS modulation in the setting of SARS-CoV-2 remain limited.ConclusionProposed interventions for SARS-CoV-2 predominantly focus on viral microbiology and aim to inhibit viral cellular injury. While these therapies are promising, immediate use may not be feasible, and the time window of their efficacy remains a major unanswered question. An alternative approach is the modulation of the specific downstream pathophysiological effects caused by the virus that lead to morbidity and mortality. We propose a preponderance of evidence that supports clinical equipoise regarding the efficacy of RAAS-based interventions, and the imminent need for a multisite randomised controlled clinical trial to evaluate the inhibition of the RAAS–SCoV axis on acute lung injury in COVID-19.

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Section: Introductionmentioning

confidence: 99%

Understanding the renin–angiotensin–aldosterone–SARS-CoV axis: a comprehensive review

et al. 2020

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“…At this point, the focus is on compounds with a demonstrated broad spectrum of antiviral activities and on drugs developed for other therapeutic purposes with evidence of acting also against coronaviruses. Several of these compounds are currently being assessed in randomized controlled clinical trials, including remdesivir (RDV; formerly GS-5734) (4).…”

mentioning

confidence: 99%

Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency

Gordon

Tchesnokov

Woolner

et al. 2020

Journal of Biological Chemistry

820

1,070

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Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the nonstructural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i؉3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2-Cmethylated compounds, including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral.

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“…Pulse oximetry, respiratory frequency, and chest X-ray films determine the clinical management of patients and the need for hospitalization. Multiple therapeutic approaches have been proposed and are being studied in clinical trials, including antiviral agents and hydroxychloroquine [12][13][14]; widespread uptake of the latter has resulted in supply restrictions for dermatologic patients with indications for antimalarials [15]. Corticosteroids are generally contraindicated in the treatment of COVID-19 [16], but the underlying cytokine storm has provided the basis for therapeutic attempts with selective immunosuppressants such as TNFα inhibitors, Janus kinase inhibitors, anti-IL-1 agents, and anti-IL-6 drugs such as tocilizumab [17,18].…”

mentioning

confidence: 99%