Coronavirus disease-19 is a highly contagious disease caused by severe acute respiratory syndrome coronavirus-2. It has shown a debilitating and catastrophic effect on the world population and is emerging as a challenging global health crisis, resulting in the overwhelmed health-care systems. Even though substantial research and unprecedented speed of vaccine development, there is still a need for better therapeutic options. The urgency to mitigate the illness has resulted in many experimental therapies and drug repurposing, leading to a better understanding of the illness and the development of novel therapies.
Keywords: 2-deoxy-D-glucose, coronavirus disease-19, interferons, molnupiravir, therapy
| Introduction|| |
The development of effective severe acute respiratory syndrome coronavirus (SARS-CoV-2) antiviral therapy remains critical for those awaiting vaccination as well as for the estimated millions of immunocompromised persons who are unlikely to respond robustly to vaccination. Moreover, the ongoing emergence and spread of immune-escape variants mean that even immunocompetent persons are likely to have higher vaccine failure rates. Antiviral therapies that target conserved viral proteins are likely to be effective against future pandemic coronaviruses. There are many new and repurposed molecules, which are currently being, investigated as therapeutic options. Here, we review a few of the newer antiviral therapies for coronavirus disease-19 (COVID-19).
| Molnupiravir|| |
β-D-N4-hydroxycytidine (NHC) is a cytidine analog that exerts its activity primarily through viral mutagenesis. Emory University scientists initially designed the molecule to inhibit the replication of the influenza virus. It has been tested for activity against other RNA viruses, including pandemic SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV).
It incorporates into new RNA strands and results in many mutations during subsequent rounds of replication., Molnupiravir or NHC can increase G to A and C to U transition mutations in replicating coronaviruses. These increases in mutation frequencies can be linked to increases in antiviral effects.
The fact that molnupiravir is not a chain terminator likely explains the mechanism by which it eludes the proof-reading function of coronavirus exonucleases. Deep sequencing studies have confirmed that viral mutagenesis is the main mechanism by which molnupiravir inhibits coronaviruses. However, there is in vitro evidence that NHC can be metabolized into deoxy-NHC and cause DNA mutations in host cells.
Remdesivir is another nucleoside analog that is currently evaluated in human trials for efficacy against SARS-CoV-2 infection. The active forms of both remdesivir and EIDD-2801 block viral RNA-dependent RNA polymerase which prevents virus replication but acts in slightly different ways, suggesting that their effects may be complementary. Another difference between both molecules is that remdesivir needs to be administered intravenously within a medical setting, whereas EIDD-2801 is orally bioavailable, and it could be taken at home, which offers the potential for treatment to be initiated earlier in the course of the disease before severe symptoms develop.
Molnupiravir has broad-spectrum antiviral activity against multiple viruses, including MERS-CoV, SARS-CoV, and SARS-CoV-2 with most EC50s below 1 μM., It is active in primary human airway epithelial cells, and it reduces virus levels, disease, and lung damage in mouse models of SARS-CoV and MERS-CoV, and in ferret models of SARS-CoV-2. A Phase I dose-ranging study of a 5-day course of oral therapy in healthy adults found no evidence of toxicity compared with a placebo group and detected levels that were expected to be efficacious based on animal model studies. A Phase II trial examined virological endpoints among persons receiving molnupiravir 200 mg BID, 400 mg BID, 800 mg BID versus placebo in 176 nonhospitalized COVID-19 patients with fever and/or signs of a respiratory illness (NCT04405570). Among 78 patients with positive baseline cultures, 6/25 (24%) placebo patients versus 0/47 pooled molnupiravir patients (P = 0.001) had positive cultures at day 5. Two large phase II/III trials in hospitalized (NCT04575584) and nonhospitalized (NCT04575597) patients with COVID-19 began in October 2020. Molnupiravir is not being studied in pregnant women or women who might become pregnant because of its mutagenic potential.
| Interferons|| |
Interferons (IFNs) are a family of cytokines with antiviral properties. They have been suggested as a potential treatment for COVID-19 because of their in vitro and in vivo antiviral properties.
In response to cellular changes suggestive of a viral infection, IFNs induce many IFN-stimulated genes encoding proteins that inhibit viral replication by slowing cellular metabolism, interfering with the membrane formation required for virus replication, and inducing cytokines that promote adaptive immunity. Although there are three IFN families, the innate immune sensing of viral nucleic acids leads specifically to the production of type I and type III IFNs.
IFN-α, IFN-β, and IFN-λ each demonstrate inhibitory activity against SARS-CoV-2 at low concentrations of 100–1000 IU/ml in Vero and Calu3 cell lines and in primary human alveolar cells., IFN-α and IFN-β have demonstrated protective effects against SARS-CoV and MERS-CoV in mice and macaques, while IFN-λ has demonstrated protective effects against SARS-CoV-2 in mice.
There has been one Phase II randomized placebo-controlled trial of a nebulized IFN-β preparation SNG001 in nonventilated hospitalized patients with COVID-19 receiving supplementary oxygen, two-phase II randomized placebo-controlled trials of subcutaneous IFN-λ in outpatients with mild disease,, two randomized open-label trials of IFN-β including the SOLIDARITY trial, one open-label trial of IFN-α, and one open-label trial of IFN-β combined with lopinavir/ritonavir and ribavirin. Nebulized IFN-β was associated with an improved outcome, as 6 of 48 patients in the IFN group versus 11 of 51 patients in the placebo group developed severe disease or died. The larger of two Phase II IFN-λ studies showed no virological benefit in outpatients with mild-to-moderate SARS-CoV-2 infection, whereas the smaller study reported lower virus loads at day 7., Among the open-label trials, the strongest signal of efficacy was a shorter time to viral clearance and more rapid clinical improvement in patients receiving IFN-β combined with lopinavir/ritonavir and ribavirin.
There is currently one ongoing Phase III trial for inhaled SNG001 (IFN-β; EUCTR2020-004743-83-GB) and one planned study for inhaled Novaferon (IFN-α) in hospitalized patients with moderate-to-severe disease (NCT04669015). Subcutaneous IFN-λ is being studied in a third phase II trial of outpatients (NCT04344600). The NIH treatment guidelines panel recommends against the use of IFNs for the treatment of severely ill patients with COVID-19 but provides no recommendation for the use of IFNs in earlier disease.
The most frequent adverse effects of interferon alfa include flu-like symptoms, nausea, fatigue, weight loss, hematological toxicities, elevated transaminases, and psychiatric problems (e.g. depression and suicidal ideation). Interferon beta is better tolerated than interferon alfa.
2-deoxy-D-glucose (2DG) is an antiglucose metabolite, a radio- chemomodifier drug used for optimizing cancer therapy. The possibility of repurposing of 2-DG, a radio- chemomodifier drug used for optimizing cancer therapy, and one of its derivative (1, 3, 4, 6- Tetra-O-acetyl-2-deoxy-D-glucopyranose, has been investigated by an in silico study.
2DG is an anti-glucose metabolite, a radio- chemo-modifier drug used for optimizing cancer therapy. The possibility of repurposing of 2-deoxy-D-glucose (2-DG), a radio- chemo-modifier drug used for optimizing cancer therapy, and one of its derivative (1, 3, 4, 6- Tetra-O-acetyl-2-deoxy-D-glucopyranose, has been investigated by an in-silico study. Since it's hypothesized that the SARS-COV-2 rapidly changes the host cell translation by altering the translation machinery, the use of 2-DG in the in silico model shows that it and its derivative, i.e., 1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose, act mostly as inhibitors by forming bonds with the molecule and proline residue of viral protease. The in-silico model stated that 2-DG showed good viral availability with fewer side effects.
At present, in India, 2-DG is developed by the Institute of Nuclear Medicine and Allied Sciences of Defense Research and Development Organization. Based on the results of Phase II and Phase III studies conducted in patients hospitalized with moderate-to-severe COVID-19 in India, 2-DG has received an EUA as an adjunct therapy in moderate-to-severe COVID-19 patients. 2-DG is administered orally/via Ryle's tube in a dose of 90 mg/kg/day.
Data suggest that the addition of 2-DG to SoC led to significantly faster clinical improvement in COVID-19 patients in the Phase II study with a median time to 2-point improvement on the WHO ordinal scale being 4.5 days in the 2-DG arm versus 8 days in the SoC arm. Phase III study of 2-DG in patients hospitalized with moderate-to-severe COVID-19:
- 2-DG led to a higher proportion of subjects improving to the score of 4 (42% vs. 31%) and 3 (11% vs. 6%) on the WHO Ordinal scale by day 3 in comparison with SoC, indicating early relief from oxygen therapy/dependence
- This improvement in oxygen dependence was observed to the same extent in patients aged 65 or above
- At discharge, 9% more patients turned RT-PCR negative in the 2-DG arm than SoC.
Data show no significant safety issues reported in both Phase II and Phase III trials (176 subjects). No related SAEs to 2-DG were reported in both trials. The demonstrated efficacy of 2-DG in early relief from oxygen dependence in moderate-to-severe COVID-19 patients indicates major benefits in the present pandemic situation.
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Apollo Hospitals, Hyderabad, Telangana
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