A SCID Mouse Model To Evaluate the Efficacy of Antivirals against SARS-CoV-2 Infection

Abdelnabi, Rana; Foo, Caroline Shi-Yan; Kaptein, Suzanne; Boudewijns, Robbert; Vangeel, Laura; Jonghe, Steven De; Jochmans, Dirk; Weynand, Birgit; Neyts, Johan

doi:10.1128/jvi.00758-22

Cited by 12 publications

(8 citation statements)

References 28 publications

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“…Our in vivo studies using K18-hACE2 mice resulted in a significant reduction of the SARS-CoV-2 lung viral loads in a lethal challenge model. The daily dose of α-DGN in these mice was 0.3 mg/kg (single dose therapeutic treatments, and once a day for prophylactic treatments), which is 1333- and 2000-fold lower than that of molnupiravir (200 mg/kg, twice a day) and nirmatrelvir (300 mg/kg, twice a day) employed in other studies via the IN route ( 31 ). In summary, we showed that α-DGN blocks SARS-CoV-2 infection at the step of cell binding, which may inhibit efficient cell-to-cell spread of the virus in lungs. Whether inhibition depends on binding of α-DGN to the host cell, to the virus, or both needs further investigation.…”

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 92%

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The α-dystroglycan N-terminus is a broad-spectrum antiviral agent against SARS-CoV-2 and enveloped viruses

Bigotti,

Klein,

Gan

et al. 2023

Preprint

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The COVID-19 pandemic has shown the need to develop effective therapeutics in preparedness for further epidemics of virus infections that pose a significant threat to human health. As a natural compound antiviral candidate, we focused on α-dystroglycan, a highly glycosylated basement membrane protein that links the extracellular matrix to the intracellular cytoskeleton. Here we show that the N-terminal fragment of α-dystroglycan (α-DGN), as produced inE. coliin the absence of post-translational modifications, blocks infection of SARS-CoV-2 in cell culture, human primary gut organoids and the lungs of transgenic mice expressing the human receptor angiotensin I-converting enzyme 2 (hACE2). Prophylactic and therapeutic administration of α-DGN reduced SARS-CoV-2 lung titres and protected the mice from respiratory symptoms and death. Recombinant α-DGN also blocked infection of a wide range of enveloped viruses including the four Dengue virus serotypes, influenza A virus, respiratory syncytial virus, tick-borne encephalitis virus, but not human adenovirus, a non-enveloped virusin vitro. This study establishes soluble recombinant α-DGN as a broad-band, natural compound candidate therapeutic against enveloped viruses.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 92%

The α-dystroglycan N-terminus is a broad-spectrum antiviral agent against SARS-CoV-2 and enveloped viruses

Bigotti,

Klein,

Gan

et al. 2023

Preprint

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“…Antiviral efficacy of the combination of NTV and RTV, the two ingredients in the Paxlovid oral COVID-19 treatment, had until recently not been reported in animals, with initial reports focusing on high-dose (300 mg/kg) NTV alone ( 10 , 92 , 93 ). Recent studies tested the NTV + RTV combination for protection against severe disease at 150 + 10 mg/kg or at 200 + 50 mg/kg in K18-hACE2 mice ( 19 , 94 , 95 ) and at 125 + 83 mg/kg or 250 + 83 mg/kg in hamsters ( 96 ).…”

Section: Discussionmentioning

confidence: 99%

An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations

Westberg,

Su,

Zou

et al. 2024

Sci. Transl. Med.

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Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 M pro more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.

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“…When we normalized the doses according to body surface areas in the individual species, they ranged from 6.25 to 3000 mg/m 2 bidaily. In four studies based on mouse models of COVID-19 including K18-hACE-2 mice, SCID mice, and lung-only mice, molnupiravir doses ranged from 20 to 500 mg/kg [38][39][40][41]. The studies in SCID mice and lung-only mice both found significantly reduced pulmonary viral titers accompanied by improved lung pathology [38,40].…”

Section: Dose Levels Of Molnupiravirmentioning

confidence: 99%

“…In four studies based on mouse models of COVID-19 including K18-hACE-2 mice, SCID mice, and lung-only mice, molnupiravir doses ranged from 20 to 500 mg/kg [38][39][40][41]. The studies in SCID mice and lung-only mice both found significantly reduced pulmonary viral titers accompanied by improved lung pathology [38,40]. In the study based on the lung-only mouse model, molnupiravir at 500 mg/kg twice daily (1500 mg/m 2 twice daily) was chosen, as this dose was assumed to provide intracellular 5 -triphosphate NHC levels similar to those in humans administered a dose of 1600 mg per day [40].…”

Section: Dose Levels Of Molnupiravirmentioning

confidence: 99%

Molnupiravir Revisited—Critical Assessment of Studies in Animal Models of COVID-19

Rasmussen,

Hansen

2023

Viruses

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Molnupiravir, a prodrug known for its broad antiviral activity, has demonstrated efficacy in animal models of COVID-19, prompting clinical trials, in which initial results indicated a significant effect against the disease. However, subsequent clinical studies did not confirm these findings, leading to the refusal of molnupiravir for permanent market authorization in many countries. This report critically assessed 22 studies published in 18 reports that investigated the efficacy of molnupiravir in animal models of COVID-19, with the purpose of determining how well the design of these models informed human studies. We found that the administered doses of molnupiravir in most studies involving animal COVID-19 models were disproportionately higher than the dose recommended for human use. Specifically, when adjusted for body surface area, over half of the doses of molnupiravir used in the animal studies exceeded twice the human dose. Direct comparison of reported drug exposure across species after oral administration of molnupiravir indicated that the antiviral efficacy of the dose recommended for human use was underestimated in some animal models and overestimated in others. Frequently, molnupiravir was given prophylactically or shortly after SARS-CoV-2 inoculation in these models, in contrast to clinical trials where such timing is not consistently achieved. Furthermore, the recommended five-day treatment duration for humans was exceeded in several animal studies. Collectively, we suggest that design elements in the animal studies under examination contributed to a preference favoring molnupiravir, and thus inflated expectations for its efficacy against COVID-19. Addressing these elements may offer strategies to enhance the clinical efficacy of molnupiravir for the treatment of COVID-19. Such strategies include dose increment, early treatment initiation, administration by inhalation, and use of the drug in antiviral combination therapy.

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A SCID Mouse Model To Evaluate the Efficacy of Antivirals against SARS-CoV-2 Infection

Cited by 12 publications

References 28 publications

The α-dystroglycan N-terminus is a broad-spectrum antiviral agent against SARS-CoV-2 and enveloped viruses

The α-dystroglycan N-terminus is a broad-spectrum antiviral agent against SARS-CoV-2 and enveloped viruses

An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations

Molnupiravir Revisited—Critical Assessment of Studies in Animal Models of COVID-19

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