Porcine deltacoronavirus (PDCoV) modulates calcium influx to favor viral replication

Bai, Dongcheng; Fang, Liurong; Xia, Sijin; Ke, Wenting; Wang, Jing; Wu, Xiaoli; Fang, Puxian; Xiao, Shaobo

doi:10.1016/j.virol.2019.10.011

Cited by 42 publications

(32 citation statements)

References 61 publications

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“…These findings open up the possibility to find dual-action steroid-remdesivir combinations that have antiviral effects early in the infection and exert immunomodulatory effects, as achieved with dexamethasone, later. Synergy with remdesivir was also observed for compounds modulating calcium channel and proton pump activity, consistent with well-established modulation and exploitation of host cell calcium signaling during infection 30,31,45 . We identified as synergistic with remdesivir the generic calcium-channel blockers nimodipine and nifedipine which are widely used as anti-hypertensives and have an excellent safety profile 36 .…”

Section: Discussionsupporting

confidence: 81%

Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells

Nguyenla

Wehri²,

Dis

et al. 2020

Preprint

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The SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with currently 29 million confirmed cases and close to a million deaths. At this time, there are no FDA-approved vaccines or therapeutics for COVID-19, but Emergency Use Authorization has been granted for remdesivir, a broad-spectrum antiviral nucleoside analog. However, remdesivir is only moderately efficacious against SARS-CoV-2 in the clinic, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. We identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5 A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir’s apparent potency 25-fold. We therefore suggest that the FDA-approved Hepatitis C therapeutics Epclusa (velpatasvir/sofosbuvir) and Zepatier (elbasvir/grazoprevir) should be fast-tracked for clinical evaluation in combination with remdesivir to improve treatment of acute SARS-CoV-2 infections.

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Section: Discussionsupporting

confidence: 81%

Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells

Nguyenla

Wehri²,

Dis

et al. 2020

Preprint

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“…17,18 While porcine deltacoronavirus (PDCoV) is an emerging enteropathogenic coronavirus that causes serious vomiting and diarrhoea in suckling piglets, a recent study reported that PDCoV modulates calcium influx to favour viral replication. 19 In this study, treatment with Ca 2+ channel blockers, particularly the L-type CCB diltiazem hydrochloride, was shown to inhibit PDCoV infection significantly. Very recently, a retrospective clinical investigation of patients with COVID-19 patients revealed that the CCB amlodipine besylate administration was associated with reduced fatality rate of patients with hypertension.…”

Section: Prospects Of Researching On Calcium Channel Drug Targets Inmentioning

confidence: 76%

COVID-19: Is it time to revisit the research on calcium channel drug targets?

Balasubramanyam

2020

EMJ Diabet

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As the COVID-19 outbreak continues to endanger global health and hamper the world economy, there are concerns and reconsiderations for medication taken by patients with cardiometabolic disorders as they are more vulnerable to COVID-19. While several articles and perspectives have dealt with the concern and safe continuation of antihypertensive drugs, there is paucity of information on calcium channel blockers (CCB). Despite the biology of calcium channel involvement in virus entry and replication, the beneficial effect of CCB is somewhat speculative and only preclinically evident. This commentary focusses on the clinical research on CCB in the context of COVID-19.

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“…It is possible that the activation of these GABA A -Rs leads to Cl - efflux, which would act to limit Ca 2+ influx in these epithelial cells. Because many viruses, including coronaviruses, elevate intracellular Ca 2+ concentrations in order to enhance viral replication (22, 23), the activation of GABA A -Rs may have limited MHV-1 replication, a possibility that we are currently investigating.…”

Section: Resultsmentioning

confidence: 99%

GABA administration prevents severe illness and death following coronavirus infection in mice

Tian

Middleton

Kaufman

2020

Preprint

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There is an urgent need for new treatments to prevent and ameliorate severe illness and death induced by SARS-CoV-2 infection in COVID-19 patients. The coronavirus mouse hepatitis virus (MHV)-1 causes pneumonitis in mice which shares many pathological characteristics with human SARS-CoV infection. Previous studies have shown that the amino acid gamma-aminobutyric acid (GABA) has anti-inflammatory effects. We tested whether oral treatment with GABA could modulate the MHV-1 induced pneumonitis in susceptible A/J mice. As expected, MHV-1-inoculated control mice became severely ill (as measured by weight loss, clinical score, and the ratio of lung weight to body weight) and >60% of them succumbed to the infection. In contrast, mice that received GABA immediately after MHV-1 inoculation became only mildly ill and all of them recovered. When GABA treatment was initiated after the appearance of illness (3 days post-MHV-1 infection), we again observed that GABA treatment significantly reduced the severity of illness and greatly increased the frequency of recovery. Therefore, the engagement of GABA receptors (GABA-Rs) prevented the MHV-1 infection-induced severe pneumonitis and death in mice. Given that GABA-R agonists, like GABA and homotaurine, are safe for human consumption, stable, inexpensive, and available worldwide, they are promising candidates to help prevent severe illness stemming from SARS-CoV-2 infection and other coronavirus strains.

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Porcine deltacoronavirus (PDCoV) modulates calcium influx to favor viral replication

Cited by 42 publications

References 61 publications

Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells

Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells

COVID-19: Is it time to revisit the research on calcium channel drug targets?

GABA administration prevents severe illness and death following coronavirus infection in mice

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