Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target Coronavirus replication.
All known recently emerged human coronaviruses probably originated in bats1. Here we used a single experimental platform based on human lung-only mice (LoM) to demonstrate efficient in vivo replication of all recently emerged human coronaviruses (SARS-CoV, MERS-CoV and SARS-CoV-2) and two highly relevant endogenous pre-pandemic SARS-like bat coronaviruses. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats harbour endogenous coronaviruses capable of direct transmission into humans. Further detailed analysis of pandemic SARS-CoV-2 in vivo infection of LoM human lung tissue showed predominant infection of human lung epithelial cells, including type II pneumocytes present in alveoli and ciliated airway cells. Acute SARS-CoV-2 infection was highly cytopathic and induced a robust and sustained type I interferon and inflammatory cytokine/chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for Coronavirus infection. Our results show that therapeutic and prophylactic administration of EIDD-2801, an oral broad spectrum antiviral currently in phase II–III clinical trials, dramatically inhibited SARS-CoV-2 replication in vivo and thus has significant potential for the prevention and treatment of COVID-19.
Thanks for bringing attention to this paper.Ygggdrasil said:A new paper published in Nature suggests that the EIDD-2801 drug (also a ribonucleoside analog like remdesivir) is effective at treating and preventing SARS-CoV-2 infection in experiments using mice:
SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801
https://www.nature.com/articles/s41586-021-03312-w
Molnupiravir, EIDD-2801/MK-4482, the prodrug of the active antiviral ribonucleoside analog ß-d-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses including severe acute respiratory syndrome Coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and seasonal and pandemic influenza viruses.
Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics.
EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure.
Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.
What I’m seeing here is an attempt to do everything possible in the Phase III to find patients in which molnupiravir will actually show a useful effect. That’s fine, but we need to realize what that means: the “molnupiravir as game-changer” story is probably now dead. There was never too much hope for that one from the beginning, honestly – there are no game-changing single-agent antiviral therapies so far, although one could always hope. The only viral diseases we can really beat down with small molecule therapy are those where we have several specifically targeted drugs, mechanistically distinct, that can be administered at the same time. That’s the case with HIV and hepatitis C. So while we could use a broad-spectrum small-molecule antiviral, we have to be prepared for it not being that great for any particular virus.
It does appear that a single mode of attack may not be enough to tackle SARS-CoV-2.Ygggdrasil said:In particular, the blog writes:...There was never too much hope for that one from the beginning, honestly – there are no game-changing single-agent antiviral therapies so far, although one could always hope. The only viral diseases we can really beat down with small molecule therapy are those where we have several specifically targeted drugs, mechanistically distinct, that can be administered at the same time. That’s the case with HIV and hepatitis C. So while we could use a broad-spectrum small-molecule antiviral, we have to be prepared for it not being that great for any particular virus.
They don't explain much about how their "quantum inspired device" works. But it should be pointed out that there was also this in silico analysis by researchers in India reported in October of last year that also suggested vitamin B12 might be a good anti-viral candidate.pinball1970 said:
Bertolin Weissmann et al said:Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp12/7/8 RNA-dependent RNA polymerase
The RdRp is one of the key druggable targets for CoVs due to its essential role in viral replication, high degree of sequence and structural conservation and the lack of homologues in human cells. Here, we have expressed, purified and biochemically characterised active SARS-CoV-2 RdRp complexes. We developed a novel fluorescence resonance energy transfer-based strand displacement assay for monitoring SARS-CoV-2 RdRp activity suitable for a high-throughput format. As part of a larger research project to identify inhibitors for all the enzymatic activities encoded by SARS-CoV-2, we used this assay to screen a custom chemical library of over 5000 approved and investigational compounds for novel SARS-CoV-2 RdRp inhibitors. We identified three novel compounds (GSK-650394, C646 and BH3I-1) and confirmed suramin and suramin-like compounds as in vitro SARS-CoV-2 RdRp activity inhibitors. We also characterised the antiviral efficacy of these drugs in cell-based assays that we developed to monitor SARS-CoV-2 growth.
AMGilead press release 22Sep21 said:In an analysis of 562 participants randomly assigned in a 1:1 ratio to receive Veklury or placebo, Veklury demonstrated a statistically significant 87% reduction in risk for the composite primary endpoint of COVID-19 related hospitalization or all-cause death by Day 28 (0.7% [2/279]) compared with placebo (5.3% [15/283]) p=0.008.
Reuters 29Sep21 said:Laboratory studies show that Merck & Co's (MRK.N) experimental oral COVID-19 antiviral drug, molnupiravir, is likely to be effective against known variants of the coronavirus, including the dominant, highly transmissible Delta, the company said on Wednesday.
Merck said:"Merck said earlier this year that a small, mid-stage trial found that after five days of molnupiravir treatment, none of the patients taking various doses of the drug tested positive for infectious virus, while 24% of placebo patients did have detectable levels.
Merck is currently conducting two Phase III trials of the antiviral it is developing with Ridgeback Biotherapeutics - one for treatment of COVID-19 and another as a preventive."
https://www.statnews.com/2021/10/01...tients-a-possible-game-changer-for-treatment/An investigational antiviral pill reduced the chances that patients newly diagnosed with Covid-19 would be hospitalized by about 50%, a finding that could give doctors a desperately needed new way to treat the sick, the drug maker Merck announced Friday.
A five-day course of molnupiravir, developed by Merck and Ridgeback Biotherapeutics, reduced both hospitalization and death compared to a placebo. In the placebo group, 53 patients, or 14.1%, were hospitalized or died. For those who received the drug, 28, or 7.3%, were hospitalized or died.
https://www.statnews.com/2021/11/30...rck-covid-pill-after-day-of-tense-discussion/On Tuesday, throughout the hearing of the advisory committee, panelists asked pointed questions of both Merck and the FDA, whose scientists had seemed to back the approval of the medicine in briefing documents released Friday. Among them was how to interpret the change in the results around the drug’s effectiveness. The early results released Oct. 1 showed a 50% reduction in hospitalization, or an absolute decrease of 7%. In the final results, the result shrank to a 30% decrease, or a 3% absolute difference in hospitalization in the full population.
Lindsey Baden of the Brigham and Women’s Hospital, the panel chair, asked early on how this could be. “Help me understand,” he said.
Nicholas Kartsonis, a Merck researcher, explained that the interim analysis was the primary analysis, but also said, at length, that Merck’s scientists had not been able to come up with clear reasons for the result. “I don’t have a satisfying answer to your question but at least that’s the totality of the data we have.”
re: Cost: Molnupiravir is about $700 per dose which compares favourably to remdesivir which costs $2300.Ygggdrasil said:@Ygggdrasil Maybe I have gotten something wrong here but it seems to me that Molnupiravir is expensive and in the end not better than already existing cheap drugs like Fluvoxamine which as we now see have shown their usefulness despite being originally dismissed in a somewhat arrogant way by many.
https://www.nature.com/articles/d41586-021-02988-4
https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00448-4/fulltext
https://www.statnews.com/2021/12/23...-pill-but-stresses-its-use-should-be-limited/The Food and Drug Administration on Thursday granted emergency authorization to Merck’s molnupiravir, an antiviral pill shown to reduce hospitalization and death in cases of Covid-19, but only in cases where other FDA-authorized Covid treatments are not accessible or clinically appropriate.
The approval comes a day after the FDA authorized an antiviral pill from Pfizer for much broader use in patients as young as 12.
“Today’s authorization provides an additional treatment option against the COVID-19 virus in the form of a pill that can be taken orally. Molnupiravir is limited to situations where other FDA-authorized treatments for COVID-19 are inaccessible or are not clinically appropriate and will be a useful treatment option for some patients with COVID-19 at high risk of hospitalization or death,” Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, said in a statement.
The COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and the elderly. We describe 4′-fluorouridine (4′-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and SARS-CoV-2 with high selectivity index in cells and human airway epithelia organoids. Polymerase inhibition within in vitro RdRP assays established for RSV and SARS-CoV-2 revealed transcriptional stalling after incorporation. Once-daily oral treatment was highly efficacious at 5 mg/kg in RSV-infected mice or 20 mg/kg in ferrets infected with different SARS-CoV-2 variants-of-concern, initiated 24 or 12 hours after infection, respectively. These properties define 4′-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2, and related RNA virus infections.
I would really like to see how effective the two drugs, molnupiravir and ritonavir, would work in combination -- one disrupting RNA replication and the protease inhibitor interfering with the protein translation. What would be the reasons for the FDA not allowing both to be given to a patient?Ygggdrasil said:Molnupiravir has received an EUA from the US FDA for use in treating COVID-19, though given that Pfizer's protease inhibitor drug seems much more effective, the FDA says its use should be limited to situations where other FDA-authorized treatments are not accessible or appropriate:
https://www.statnews.com/2021/12/23...-pill-but-stresses-its-use-should-be-limited/
The protease inhibitor drug showed 89% reduction in hospitalizations in phase 3 clinical trials versus a 30% reduction in hospitalizations for molnupiravir. The clinical trial for fluvoxamine cited by @artis above showed a 32% decrease in hospitalizations, similar to the efficacy of molnupiravir.
I would expect that the combination has to be tested to ensure no severe side-effects, in addition to an efficacious treatment.Andrew Mason said:What would be the reasons for the FDA not allowing both to be given to a patient?
https://www.fda.gov/news-events/pre...rizes-first-oral-antiviral-treatment-covid-19Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for Pfizer’s Paxlovid (nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use) for the treatment of mild-to-moderate Coronavirus disease (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kilograms or about 88 pounds) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. Paxlovid is available by prescription only and should be initiated as soon as possible after diagnosis of COVID-19 and within five days of symptom onset.
The protease inhibitor drug (nirmatrelvir) already seems very effective at preventing hospitalizations (89%), so it would be difficult to assess whether the combination helps to improve efficacy. One potential benefit from combining them would be to help evade drug resistance (as in the case of antiretroviral drug cocktails used for anti-HIV therapy). However, molnupiravir acts to increase the mutation rate of the virus, so it's possible that the drug could accelerate resistance to nirmatrelvir. While unlikely, this issue should at least be studies before clinical trials of the combination therapy begin. Similarly, clinical trials of the combination should be performed to see if the combination has any unexpected adverse effects (esp. because we have very little data on the use of these drugs in the real world versus more established drugs where real world data might have already provided information on interactions with other types of medications).Andrew Mason said:I would really like to see how effective the two drugs, molnupiravir and ritonavir, would work in combination -- one disrupting RNA replication and the protease inhibitor interfering with the protein translation. What would be the reasons for the FDA not allowing both to be given to a patient?
AM
In my inexpert opinion, MCAs are probably a good post-vaccination temporary enhancement for persons at risk of encountering mutated versions of SARS-CoV-2, and may be beneficial for persons using protease inhibitors (I don't know whether any PIs are in clinical trial yet).Ygggdrasil said:The protease inhibitor drug (nirmatrelvir) already seems very effective at preventing hospitalizations (89%), so it would be difficult to assess whether the combination helps to improve efficacy. One potential benefit from combining them would be to help evade drug resistance (as in the case of antiretroviral drug cocktails used for anti-HIV therapy). However, molnupiravir acts to increase the mutation rate of the virus, so it's possible that the drug could accelerate resistance to nirmatrelvir. While unlikely, this issue should at least be studies before clinical trials of the combination therapy begin. Similarly, clinical trials of the combination should be performed to see if the combination has any unexpected adverse effects (esp. because we have very little data on the use of these drugs in the real world versus more established drugs where real world data might have already provided information on interactions with other types of medications).
