Molnupiravir — A Step toward Orally Bioavailable Therapies for Covid-19

Whitley, Richard J.

doi:10.1056/nejme2117814

Cited by 51 publications

(39 citation statements)

References 10 publications

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“…The combination of sphingolipid and sphingolipid metabolizing enzymes as biomarkers have the potential as a diagnostic marker and may help to prioritize those patients for treatment with medication including approved SARS-CoV-2-neutralizing monoclonal antibodies (Kreuzberger et al 2021) or newly developed antiviral drugs like molnupiravir (Whitley 2021) or paxlovid (Wang and Yang 2021). These treatments suffer from limited supplies and lower efficacy against variants such as omicron; they are also associated with high cost and side effects and thus would be applied specifically in high-risk cases.…”

Section: Discussionmentioning

confidence: 99%

COVID-19 and its clinical severity are associated with alterations of plasma sphingolipids and enzyme activities of sphingomyelinase and ceramidase

Mühle

Kremer

Vetter

et al. 2022

Preprint

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In the current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19), a better understanding of the underlying mechanisms is essential to reduce morbidity and mortality and treat post-COVID-19 disease. Here, we analyzed alterations of sphingolipids and their metabolizing enzymes in 125 men and 74 women tested positive for SARS-CoV-2 and hospitalized with mild, moderate or severe symptoms or after convalescence. The activities of acid and neutral sphingomyelinases (ASM, NSM), which hydrolyze sphingomyelin to ceramide, were significantly increased in COVID-19 patients, while the activity of neutral ceramidase (NC), which hydrolyzes ceramide to sphingosine, was reduced. These alterations could each contribute to elevated ceramide levels in patients. Accordingly, liquid chromatography tandem-mass spectrometry (LC-MS/MS) yielded increased levels of ceramides 16:0 and 18:0 with highest levels in severely affected patients and similar effects for dihydroceramides 16:0 and 18:0, whereas levels of (dihydro-)ceramides 24:0 were reduced. Furthermore, sphingomyelin 20:0; 22:0 and 24:0 as substrates of ASM and NSM as well as their dihydrosphingomyelin counterparts were reduced in patients as well as sphingosine-1-phosphate further downstream of NC activity. Effects of NSM, NC, ceramides and sphingomyelins remained significant after Bonferroni correction. SARS-CoV-2 antibody levels in convalescent patients were associated with age but none of the sphingolipid parameters. Based on our data, COVID-19 is associated with a dysregulation of sphingolipid homeostasis in a severity-dependent manner, particularly focused around a reduction of sphingomyelins and an accumulation of ceramides by increased enzyme activities leading to ceramide elevation (ASM, NSM) combined with a decreased activity of enzymes (NC) reducing ceramide levels. The potential of a combined sphingolipid/enzyme pattern as a diagnostic and prognostic marker and therapeutic target deserves further exploration.

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Section: Discussionmentioning

confidence: 99%

COVID-19 and its clinical severity are associated with alterations of plasma sphingolipids and enzyme activities of sphingomyelinase and ceramidase

Mühle

Kremer

Vetter

et al. 2022

Preprint

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“…Recently, Merck and Co., in collaboration with Ridgeback Therapeutics, have developed an antiviral oral drug, named Molnupiravir, for the treatment of COVID-19 patients, which shows promising effects against infections and reduces hospitalizations and fatal outcomes by 50%. Of note, the European Medicines Agency has issued emergency authorization of Molnupiravir (also known as Lagevrio or MK4482) for adult COVID-19 patients suffering with increased complications and illnesses [ 156 , 157 ]. The FDA has also recently approved an antiviral oral drug, developed by Pfizer Inc., known as Paxlovid (Nirmatrelvir/Ritonavir), which reduces the risk of hospitalizations and deaths by 89% [ 158 , 159 ].…”

Section: Therapeutic Approaches For the Prevention And Treatment Of C...mentioning

confidence: 99%

Healthy Immunity on Preventive Medicine for Combating COVID-19

2022

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Immunomodulation is influenced by the consumption of nutrients, and healthy immunity is pivotal to defending an individual from a variety of pathogens. The immune system is a network of intricately regulated biological processes that is comprised of many organs, cellular structures, and signaling molecules. A balanced diet, rich in vitamins, minerals, and antioxidants, is key to a strengthened immune system and, thus, crucial to proper functioning of various physiological activities. Conversely, deficiencies of these micronutrients, involving impaired immunity, are linked to numerous health complications, along with a host of pathologies. Coronavirus disease 2019 (COVID-19) is a dangerous infectious disease caused by a β-form of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its genomic variants, which enter host cells upon binding to the angiotensin converting enzyme 2 receptors, and is associated with substantial morbidities and mortalities globally. Patients afflicted with COVID-19 display asymptomatic to severe symptoms, occurrences of which are multifactorial and include diverse immune responses, sex and gender differences, aging, and underlying medical conditions. Geriatric populations, especially men in comparison to women, regardless of their states, are most vulnerable to severe COVID-19-associated infections and complications, with fatal outcomes. Advances in genomic and proteomic technologies help one understand molecular events, including host–pathogen interactions and pathogenesis of COVID-19 and, subsequently, have developed a variety of preventive measures urgently, ranging from mask wearing to vaccination to medication. Despite these approaches, no unique strategy is available today that can effectively prevent and/or treat this hostile disease. As a consequence, the maintenance of a boosted immune system could be considered a high priority of preventive medicine for combating COVID-19. Herein, we discuss the current level of understanding underlining the contribution of healthy immunity and its relevance to COVID-19 molecular pathogenesis, and potential therapeutic strategies, in the management of this devastating disease.

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“… 2 - 11 Unlike other ribonucleoside analogue antiviral agents, key to MOV’s efficiency in inducing catastrophic viral mutagenesis is its ability to evade SARS-CoV-2 exonuclease proofreading activity. 8 MOV has shown promising phase 3 MOVe-OUT clinical trial results where early treatment “reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19.” 12 , 13 Importantly, MOV was effective against all three SARS-CoV-2 variants of concern (delta, gamma, and mu) which were tested. 12 , 13 …”

Section: Introductionmentioning

confidence: 99%

“… 8 MOV has shown promising phase 3 MOVe-OUT clinical trial results where early treatment “reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19.” 12 , 13 Importantly, MOV was effective against all three SARS-CoV-2 variants of concern (delta, gamma, and mu) which were tested. 12 , 13 …”

Section: Introductionmentioning

confidence: 99%

Molnupiravir Does Not Induce Mutagenesis in Host Lung Cells during SARS-CoV-2 Treatment

Githaka

2022

Bioinform Biol Insights

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As SARS-CoV-2 continues to evolve and spread with the emergence of new variants, interest in small molecules with broad-spectrum antiviral activity has grown. One such molecule, Molnupiravir (MOV; other names: MK-4482, EIDD-2801), a ribonucleoside analogue, has emerged as an effective SARS-CoV-2 treatment by inducing catastrophic viral mutagenesis during replication. However, there are growing concerns as MOV’s potential to induce host DNA mutagenesis remains an open question. Analysis of RNA-seq data from SARS-CoV-2–infected MOV-treated golden hamster lung biopsies confirmed MOV’s efficiency in stopping SARS-CoV-2 replication. Importantly, MOV treatment did not increase mutations in the host lung cells. This finding calls for additional mutation calls on host biopsies from more proliferative tissues to fully explore MOV’s hypothesized mutagenic risk.

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Molnupiravir — A Step toward Orally Bioavailable Therapies for Covid-19

Cited by 51 publications

References 10 publications

COVID-19 and its clinical severity are associated with alterations of plasma sphingolipids and enzyme activities of sphingomyelinase and ceramidase

COVID-19 and its clinical severity are associated with alterations of plasma sphingolipids and enzyme activities of sphingomyelinase and ceramidase

Healthy Immunity on Preventive Medicine for Combating COVID-19

Molnupiravir Does Not Induce Mutagenesis in Host Lung Cells during SARS-CoV-2 Treatment

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