molnupiravir and favipiravir

This review considers antiviral nucleoside analog drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS-CoV or SARS-CoV-2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro "host" cell mutagenicity of its active principle, β-d-N4-hydroxycytidine, we have reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, that is, ribavirin, favipiravir, and 5-(2-chloroethyl)-2'-deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human genotoxicity data and follow-up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG-A and error corrected next generation sequencing (duplex sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis.

Topics: Amides; Antiviral Agents; COVID-19 Drug Treatment; Cytidine; Deoxyuridine; DNA Damage; Genome, Human; Humans; Hydroxylamines; Mutagenesis; Nucleosides; Pyrazines; Ribavirin; SARS-CoV-2

Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; COVID-19 Drug Treatment; Cytidine; Drug Development; Drug Repositioning; Humans; Hydroxylamines; Pyrazines; RNA-Dependent RNA Polymerase; SARS-CoV-2

Influenza viruses are a major threat to human health globally. In addition to further improving vaccine prophylaxis, disease management through antiviral therapeutics constitutes an important component of the current intervention strategy to prevent advance to complicated disease and reduce case-fatality rates. Standard-of-care is treatment with neuraminidase inhibitors that prevent viral dissemination. In 2018, the first mechanistically new influenza drug class for the treatment of uncomplicated seasonal influenza in 2 decades was approved for human use. Targeting the PA endonuclease subunit of the viral polymerase complex, this class suppresses viral replication. However, the genetic barrier against viral resistance to both drug classes is low, pre-existing resistance is observed in circulating strains, and resistant viruses are pathogenic and transmit efficiently. Addressing the resistance problem has emerged as an important objective for the development of next-generation influenza virus therapeutics. This review will discuss the status of influenza therapeutics including the endonuclease inhibitor baloxavir marboxil after its first year of clinical use and evaluate a subset of direct-acting antiviral candidates in different stages of preclinical and clinical development.

Topics: Amides; Antibodies, Neutralizing; Antiviral Agents; Cytidine; Dibenzothiepins; Drug Resistance, Viral; Humans; Hydroxylamines; Influenza, Human; Morpholines; Neuraminidase; Oxazines; Pyrazines; Pyridines; Pyridones; Ribonucleosides; RNA-Dependent RNA Polymerase; Thiepins; Triazines; Virus Replication

The coronavirus disease 2019 (COVID-19) that is wreaking havoc on worldwide public health and economies has heightened awareness about the lack of effective antiviral treatments for human coronaviruses (CoVs). Many current antivirals, notably nucleoside analogs (NAs), exert their effect by incorporation into viral genomes and subsequent disruption of viral replication and fidelity. The development of anti-CoV drugs has long been hindered by the capacity of CoVs to proofread and remove mismatched nucleotides during genome replication and transcription. Here, we review the molecular basis of the CoV proofreading complex and evaluate its potential as a drug target. We also consider existing nucleoside analogs and novel genomic techniques as potential anti-CoV therapeutics that could be used individually or in combination to target the proofreading mechanism.

Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; Cytidine; Genome, Viral; Humans; Hydroxylamines; Molecular Targeted Therapy; Mutation; Pandemics; Pneumonia, Viral; Pyrazines; Ribonucleosides; RNA, Viral; SARS-CoV-2; Severity of Illness Index; Transcription, Genetic; Viral Nonstructural Proteins; Virus Replication

Coronavirus disease 2019, the disease caused by the severe acute respiratory syndrome coronavirus 2 virus, was first identified in the Hubei Province of China in late 2019. Currently, the only role for therapy is treatment of the disease, as opposed to postexposure prophylaxis, however multiple clinical trials are currently ongoing for both treatment and prophylaxis. Treating coronavirus disease 2019 relies on two components; the first is inhibition of the viral entrance and replication within the body and the second is inhibition of an exacerbated immune response which can be seen in patients with severe disease. Many drugs have shown in vitro antiviral activity; however, clinical trials have not been as promising. This review summarizes the current data for the most commonly used drugs for coronavirus disease 2019 and will cover the unique factors that may affect the dosing of these medications in patients with CKD. While clinical trials are ongoing, most are in patients with normal kidney function. During a pandemic, when patients with CKD are at higher risk of both infection and death, it is imperative to include patients these patients in the clinical trials.

Topics: Adenosine Monophosphate; Alanine; Amides; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Antiviral Agents; Chloroquine; COVID-19; COVID-19 Drug Treatment; COVID-19 Serotherapy; COVID-19 Vaccines; Creatinine; Cytidine; Dexamethasone; Drug Combinations; Drug Interactions; Humans; Hydroxychloroquine; Hydroxylamines; Immunization, Passive; Interferons; Janus Kinase Inhibitors; Lopinavir; Pyrazines; Renal Elimination; Renal Insufficiency, Chronic; Renal Replacement Therapy; Ribavirin; Ritonavir; SARS-CoV-2

There are a number of uncertainties regarding plasma protein binding and blood distribution of the active drugs favipiravir (FAVI), molnupiravir (MOLNU) and imatinib (IMA), which were recently proposed as therapeutics for the treatment of COVID-19 disease. Therefore, proton dissociation processes, solubility, lipophilicity, and serum protein binding of these three substances were investigated in detail. The drugs display various degrees of lipophilicity at gastric (pH 2.0) and blood pH (pH 7.4). The determined p

Topics: Blood Proteins; COVID-19; Humans; Imatinib Mesylate; Orosomucoid; Plasma; Protein Binding; SARS-CoV-2; Serum Albumin, Human

The Covid-19 pandemic has affected the global population since 2019. The rapid development and approval of vaccines has brought relief. Yet, effective cures are still being researched. Even if the pandemic situation may end, SARS-CoV-2 will remain and, thus, continued application of the drugs will lead to emissions of the active ingredients into the aquatic environment, as with other anthropogenic micropollutants. However, a general method for trace analysis of antiviral drugs is still missing. To this purpose, favipiravir, remdesivir, its active metabolite GS-441524, molnupiravir and its active metabolite EIDD-1931 were selected as representative analytes. A method was developed based on solid phase extraction and high-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight high-resolution mass spectrometry. Optimization comprised the choice of chromatographic columns, elution gradient, mass spectrometry and tandem mass spectrometry parameters. Solid phase extraction proved suitable for increase in limits of detection and quantitation. amelioration of the limits of detection and quantitation. Matrix effects were investigated applying the optimized method to a wastewater sample with added virustatics. All five compounds could be separated with reversed phase chromatography, whereas EIDD-1931 profited from hydrophilic interaction liquid chromatography. The optimized method yielded limits of detection and quantification of 2.1·10

Topics: Chromatography, High Pressure Liquid; COVID-19; Humans; Pandemics; Pharmaceutical Preparations; SARS-CoV-2; Solid Phase Extraction; Tandem Mass Spectrometry

Following the spread of the COVID-19 pandemic crisis, a race was initiated to find a successful regimen for postinfections. Among those trials, a recent study declared the efficacy of an antiviral combination of favipiravir (FAV) and molnupiravir (MLP). The combined regimen helped in a successful 60% eradication of the SARS-CoV-2 virus from the lungs of studied hamster models. Moreover, it prevented viral transmission to cohosted sentinels. Because both medications are orally bioavailable, the coformulation of FAV and MLP can be predicted. The developed study is aimed at developing new green and simple methods for the simultaneous determination of FAV and MLP and then at their application in the study of their dissolution behavior if coformulated together. A green micellar HPLC method was validated using an RP-C18 core-shell column (5 μm, 150 × 4.6 mm) and an isocratic mixed micellar mobile phase composed of 0.1 M SDS, 0.01 M Brij-35, and 0.02 M monobasic potassium phosphate mixture and adjusted to pH 3.1 at 1.0 mL min

Topics: Amides; Antiviral Agents; Chromatography, High Pressure Liquid; COVID-19 Drug Treatment; Cytidine; Humans; Hydroxylamines; Micelles; Pandemics; Pyrazines; Reproducibility of Results; SARS-CoV-2; Spectrophotometry, Ultraviolet

Favipiravir, molnupiravir, and ritonavir have been recently approved as the first oral antivirals for treatment of SARS-CoV-2 viral infections. Their combination was reported in several clinical studies, alternatively, to enhance the viral eradication and improve patient's recovery times and rates. Being all orally administered, therefore, the development of new sensitive and validated methodologies for their simultaneous determination is a necessitate. In the proposed research, a sensitive, selective, and simple high-performance thin layer chromatography method was developed and validated for determination of favipiravir, molnupiravir, and ritonavir. Silica gel 60F254 thin layer chromatography plates were used as stationary phase for this separation using mobile phase composed of methylene chloride:ethyl acetate:methanol:25% ammonia (6:3:4:1, v/v/v/v). Densitometric detection was performed at wavelength 289 nm. Peaks of favipiravir, molnupiravir, and ritonavir were resolved at retention factors 0.22, 0.42, and 0.63, respectively. The proposed method was found linear within the specified ranges of 3.75-100.00 μg/mL for molnupiravir and favipiravir, and 2.75-100.00 μg/mL for ritonavir. Limits of detection were found to be 1.12, 1.21, and 0.89 μg/mL for favipiravir, molnupiravir, and ritonavir, respectively. This is the first method to be reported for the simultaneous determination of the cited three antiviral drugs. The method was assessed on novel greenness metrics.

Topics: Amides; Antiviral Agents; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; COVID-19 Drug Treatment; Cytidine; Drug Compounding; Humans; Hydroxylamines; Pyrazines; Reproducibility of Results; Ritonavir; SARS-CoV-2

In the wake of SARS-CoV-2's global spread, human activities from health to social life to education have been affected. Favipiravir and Molnupiravir exhibited novel hexokinase inhibition and we discuss advantages of this property in their COVID-19 inhibition potential.. This paper describes molecular docking data of human hexokinase II with Favipiravir, Cyan 20, Remdesivir, 2DG, and Molnupiravir along with hexokinase inhibition assays.. Favipiravir, an antiviral drug previously cleared for treating the flu and ebola, has shown some promise in early trials to treat COVID-19. We observed potent human hexokinase inhibiting potential of Favipiravir (50%) as against 4% and merely 0.3% hexokinase inhibition with Molnupiravir and 2 Deoxy D glucose at 0.1 mM concentration supported by molecular docking studies.. Favipiravir could continue to be part of the COVID-19 treatment regimen due to its resistance to host esterases, hexokinase inhibition potential and proven safety through human trials.

Topics: Amides; Antiviral Agents; COVID-19 Drug Treatment; Cytidine; Deoxyglucose; Hexokinase; Humans; Hydroxylamines; Molecular Docking Simulation; Pyrazines; SARS-CoV-2

The virus that causes Ebola is fatal. Although many researchers have attempted to contain this deadly infection, the fatality rate remains high. The atom-pair fingerprint technique was used to compare drugs suggested for the treatment of Ebola or those that are currently being tested in clinical settings. Subsequently, using scaffold network graph (SNG) methods, the molecular and structural scaffolds of the drugs chosen based on these similar results were created, and the drug structures were examined. Public databases (PubChem and DrugBank) and literature regarding Ebola treatment were used in the analysis. Graphical representations of the molecular architecture and core structures of the drugs with the highest similarity to Food and Drug Administration (FDA)-approved drugs were produced using the SNG method. The combination of molnupiravir, the first licensed oral medication candidate for COVID-19, and favipiravir, employed in other viral outbreaks, should be further researched for treating Ebola, as observed in our study. We also believe that chemists will benefit from understanding the core structure(s) of medication molecules effective against the Ebola virus, their inhibitors, and the chemical structure similarities of existing pharmaceuticals utilized to build alternative drugs or drug combinations.

Topics: Antiviral Agents; COVID-19; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Molecular Structure; Pharmaceutical Preparations; United States

Favipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV-2. First efficacy data have been recently reported in COVID-19 patients.. We here report on the combined antiviral effect of both drugs in a SARS-CoV-2 Syrian hamster infection model. The infected hamsters were treated twice daily with the vehicle (the control group) or a suboptimal dose of each compound or a combination of both compounds.. When animals were treated with a combination of suboptimal doses of Molnupiravir and Favipiravir at the time of infection, a marked combined potency at endpoint is observed. Infectious virus titers in the lungs of animals treated with the combination are reduced by ∼5 log10 and infectious virus are no longer detected in the lungs of >60% of treated animals. When start of treatment was delayed with one day a reduction of titers in the lungs of 2.4 log10 was achieved. Moreover, treatment of infected animals nearly completely prevented transmission to co-housed untreated sentinels. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs of treated animals. In the combo-treated hamsters, an increased frequency of C-to-T mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination.. Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir/Favipiravir in the treatment of COVID-19.. stated in the acknowledgment.

Topics: Amides; Animals; Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Cytidine; Disease Models, Animal; Drug Therapy, Combination; Female; Hydroxylamines; Lung; Mesocricetus; Pyrazines; RNA, Viral; Treatment Outcome; Viral Load

Topics: Africa; Amides; Amodiaquine; Artesunate; Atazanavir Sulfate; Carbamates; Clinical Trials as Topic; COVID-19; COVID-19 Drug Treatment; COVID-19 Vaccines; Cytidine; Drug Approval; Drug Evaluation, Preclinical; Drug Repositioning; Drug Therapy, Combination; Humans; Hydroxylamines; Imidazoles; Ivermectin; Naphthyridines; Nitro Compounds; Pregnenediones; Pyrazines; Pyrrolidines; Ritonavir; Sample Size; Thiazoles; Valine; World Health Organization

Topics: Amides; Animals; Antiviral Agents; COVID-19 Drug Treatment; Cricetinae; Cytidine; Drug Synergism; Drug Therapy, Combination; Humans; Hydroxylamines; Pyrazines; SARS-CoV-2