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Viruses Sep 2023Following virus infections, type I interferons are synthesized to induce the expression of antiviral molecules and interfere with virus replication. The importance of... (Review)
Review
Following virus infections, type I interferons are synthesized to induce the expression of antiviral molecules and interfere with virus replication. The importance of early antiviral type I IFN response against virus invasion has been emphasized during COVID-19 as well as in studies on the microbiome. Further, type I IFNs can directly act on various immune cells to enhance protective host immune responses to viral infections. However, accumulating data indicate that IFN responses can be harmful to the host by instigating inflammatory responses or inducing T cell suppression during virus infections. Also, inhibition of lymphocyte and dendritic cell development can be caused by type I IFN, which is independent of the traditional signal transducer and activator of transcription 1 signaling. Additionally, IFNs were shown to impair airway epithelial cell proliferation, which may affect late-stage lung tissue recovery from the infection. As such, type I IFN-virus interaction research is diverse, including host antiviral innate immune mechanisms in cells, viral strategies of IFN evasion, protective immunity, excessive inflammation, immune suppression, and regulation of tissue repair. In this report, these IFN activities are summarized with an emphasis placed on the functions of type I IFNs recently observed during acute or chronic virus infections.
Topics: Humans; Interferon Type I; COVID-19; Virus Diseases; Antiviral Agents; Virus Replication
PubMed: 37766322
DOI: 10.3390/v15091916 -
The Lancet. Infectious Diseases Jan 2024Molnupiravir and ritonavir-boosted nirmatrelvir are the two leading oral COVID-19 antiviral treatments, but their antiviral activities in patients have not been compared... (Randomized Controlled Trial)
Randomized Controlled Trial
Antiviral efficacy of molnupiravir versus ritonavir-boosted nirmatrelvir in patients with early symptomatic COVID-19 (PLATCOV): an open-label, phase 2, randomised, controlled, adaptive trial.
BACKGROUND
Molnupiravir and ritonavir-boosted nirmatrelvir are the two leading oral COVID-19 antiviral treatments, but their antiviral activities in patients have not been compared directly. The aim of this ongoing platform trial is to compare different antiviral treatments using the rate of viral clearance as the measure of antiviral effect.
METHODS
PLATCOV is an open-label, multicentre, phase 2, randomised, controlled, adaptive pharmacometric platform trial running in Thailand, Brazil, Pakistan, and Laos. The component of the trial reported here was conducted in the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. We recruited low-risk adult patients aged 18-50 years with early symptomatic COVID-19 (<4 days of symptoms). Eligible patients were randomly assigned using block randomisation via a centralised web app to one of seven treatment groups: molnupiravir, ritonavir-boosted nirmatrelvir, casirivimab-imdevimab, tixagevimab-cilgavimab, favipiravir, fluoxetine, or no study drug. The no study drug group comprised a minimum proportion of 20% of patients at all times, with uniform randomisation ratios applied across the active treatment groups. Results for the concurrently randomised molnupiravir, ritonavir-boosted nirmatrelvir, and no study drug groups are reported here. The primary endpoint was the rate of oropharyngeal viral clearance assessed in a modified intention-to-treat population, defined as patients with more than 2 days of follow-up. Safety was assessed in all participants who took at least one dose of the medication. The viral clearance rate was derived under a Bayesian hierarchical linear model fitted to the log viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 1 week (18 measurements). Treatment groups with a probability of more than 0·9 that viral clearance was accelerated by more than 20% compared with no drug entered a non-inferiority comparison (with a 10% non-inferiority margin) compared with the platform's current most effective drug. This ongoing trial is registered at ClinicalTrials.gov, NCT05041907.
FINDINGS
Between June 6, 2022, and Feb 23, 2023, 209 patients in Thailand were enrolled and concurrently randomly assigned to molnupiravir (n=65), ritonavir-boosted nirmatrelvir (n=59), or no study drug (n=85). 129 (62%) of the patients were female and 80 (38%) were male. Relative to the no study drug group, the rates of viral clearance were 37% (95% credible interval 16-65) faster with molnupiravir and 84% (54-119) faster with ritonavir-boosted nirmatrelvir. In the non-inferiority comparison, viral clearance was 25% (10-38) slower with molnupiravir than ritonavir-boosted nirmatrelvir. Molnupiravir was removed from the study platform when it reached the prespecified inferiority margin of 10% compared with ritonavir-boosted nirmatrelvir. Median estimated viral clearance half-lives were 8·5 h (IQR 6·7-10·1) with ritonavir-boosted nirmatrelvir, 11·6 h (8·6-15·4) with molnupiravir, and 15·5 h (11·9-21·2) with no study drug. Viral rebound occurred more frequently following nirmatrelvir (six [10%] of 58) compared with the no study drug (one [1%] of 84; p=0·018) or the molnupiravir (one [2%] of 65; p=0·051) groups. Persistent infections following molnupiravir had more viral mutations (three of nine patients had an increased number of single nucleotide polymorphisms in samples collected at 7 or more days compared with those at baseline) than after nirmatrelvir (zero of three) or no study drug (zero of 19). There were no adverse events of grade 3 or worse, or serious adverse events in any of the reported treatment groups.
INTERPRETATION
Both molnupiravir and ritonavir-boosted nirmatrelvir accelerate oropharyngeal SARS-CoV-2 viral clearance in patients with COVID-19, but the antiviral effect of ritonavir-boosted nirmatrelvir was substantially greater. Measurement of oropharyngeal viral clearance rates provides a rapid and well tolerated approach to the assessment and comparison of antiviral drugs in patients with COVID-19. It should be evaluated in other acute viral respiratory infections.
FUNDING
Wellcome Trust through the COVID-19 Therapeutics Accelerator.
Topics: Adult; Humans; Male; Female; Ritonavir; Anti-HIV Agents; HIV Infections; Bayes Theorem; COVID-19; HIV-1; Treatment Outcome; SARS-CoV-2; Thailand; COVID-19 Drug Treatment; Antiviral Agents
PubMed: 37778363
DOI: 10.1016/S1473-3099(23)00493-0 -
Viruses Dec 2023Ferroptosis is a novelty form of regulated cell death, and it is mainly characterized by iron accumulation and lipid peroxidation in the cells. Its underlying mechanism... (Review)
Review
Ferroptosis is a novelty form of regulated cell death, and it is mainly characterized by iron accumulation and lipid peroxidation in the cells. Its underlying mechanism is related to the amino acid, iron, and lipid metabolisms. During viral infection, pathogenic microorganisms have evolved to interfere with ferroptosis, and ferroptosis is often manipulated by viruses to regulate host cell servicing for viral reproduction. Therefore, this review provides a comprehensive overview of the mechanisms underlying ferroptosis, elucidates the intricate signaling pathways involved, and explores the pivotal role of ferroptosis in the pathogenesis of viral infections. By enhancing our understanding of ferroptosis, novel therapeutic strategies can be devised to effectively prevent and treat diseases associated with this process. Furthermore, unraveling the developmental mechanisms through which viral infections exploit ferroptosis will facilitate development of innovative antiviral agents.
Topics: Humans; Ferroptosis; Amino Acids; Antiviral Agents; Iron; Virus Diseases
PubMed: 38140616
DOI: 10.3390/v15122373 -
Nature Communications Oct 2023The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the...
The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CL) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CL with an enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that simnotrelvir is a potent pan-CoV 3CL inhibitor but has high selectivity. It effectively blocks replications of SARS-CoV-2 variants in cell-based assays and exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2 Delta infection in which it not only significantly reduces lung viral loads but also eliminates the virus from brains. The discovery of simnotrelvir thereby highlights the utility of structure-based development of marked protease inhibitors for providing a small molecule therapeutic effectively combatting human coronaviruses.
Topics: Mice; Female; Male; Animals; Humans; Rats; SARS-CoV-2; Protease Inhibitors; COVID-19; Antiviral Agents; Enzyme Inhibitors
PubMed: 37833261
DOI: 10.1038/s41467-023-42102-y -
International Journal of Molecular... Sep 2023Infection with Ebola virus (EBOV) is responsible for hemorrhagic fever in humans with a high mortality rate. Combined efforts of prevention and therapeutic intervention...
Infection with Ebola virus (EBOV) is responsible for hemorrhagic fever in humans with a high mortality rate. Combined efforts of prevention and therapeutic intervention are required to tackle highly variable RNA viruses, whose infections often lead to outbreaks. Here, we have screened the 2P2I chemical library using a nanoluciferase-based protein complementation assay (NPCA) and isolated two compounds that disrupt the interaction of the EBOV protein fragment VP35IID with the N-terminus of the dsRNA-binding proteins PKR and PACT, involved in IFN response and/or intrinsic immunity, respectively. The two compounds inhibited EBOV infection in cell culture as well as infection by measles virus (MV) independently of IFN induction. Consequently, we propose that the compounds are antiviral by restoring intrinsic immunity driven by PACT. Given that PACT is highly conserved across mammals, our data support further testing of the compounds in other species, as well as against other negative-sense RNA viruses.
Topics: Humans; Animals; Hemorrhagic Fever, Ebola; Ebolavirus; Antiviral Agents; Mammals
PubMed: 37834238
DOI: 10.3390/ijms241914791 -
Molecules (Basel, Switzerland) Nov 2023The results of the most recent investigation of triterpenoid-based antiviral agents namely in the HIV-1 and HSV-1 treatment were reviewed and summarized. Several key... (Review)
Review
The results of the most recent investigation of triterpenoid-based antiviral agents namely in the HIV-1 and HSV-1 treatment were reviewed and summarized. Several key historical achievements are included to stress consequences and continuity in this research. Most of the agents studied belong to a series of compounds derived from betulin or betulinic acid, and their synthetic derivative is called bevirimat. A termination of clinical trials of bevirimat in Phase IIb initiated a search for more successful compounds partly derived from bevirimat or designed independently of bevirimat structure. Surprisingly, a majority of bevirimat mimics are derivatives of betulinic acid, while other plant triterpenoids, such as ursolic acid, oleanolic acid, glycyrrhetinic acid, or other miscellaneous triterpenoids, are relatively rarely involved in a search for a novel antiviral agent. Therefore, this review article is divided into three parts based on the leading triterpenoid core structure.
Topics: Triterpenes; Antiviral Agents; Betulinic Acid; Pentacyclic Triterpenes; Plants
PubMed: 38067449
DOI: 10.3390/molecules28237718 -
Molecular Pharmaceutics Aug 2023Human viral oncogenesis is a complex phenomenon and a major contributor to the global cancer burden. Several recent findings revealed cellular and molecular pathways... (Review)
Review
Human viral oncogenesis is a complex phenomenon and a major contributor to the global cancer burden. Several recent findings revealed cellular and molecular pathways that promote the development and initiation of malignancy when viruses cause an infection. Even, antiviral treatment has become an approach to eliminate the viral infections and prevent the activation of oncogenesis. Therefore, for a better understanding, the molecular pathogenesis of various oncogenic viruses like, hepatitis virus, human immunodeficiency viral (HIV), human papillomavirus (HPV), herpes simplex virus (HSV), and Epstein-Barr virus (EBV), could be explored, especially, to expand many potent antivirals that may escalate the apoptosis of infected malignant cells while sparing normal and healthy ones. Moreover, contemporary therapies, such as engineered antibodies antiviral agents targeting signaling pathways and cell biomarkers, could inhibit viral oncogenesis. This review elaborates the recent advancements in both natural and synthetic antivirals to control viral oncogenesis. The study also highlights the challenges and future perspectives of using antivirals in viral oncogenesis.
Topics: Humans; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Carcinogenesis; Neoplasms; Antiviral Agents
PubMed: 37486263
DOI: 10.1021/acs.molpharmaceut.2c01080 -
Antiviral Research Aug 2023Many poxviruses are significant human and animal pathogens, including viruses that cause smallpox and mpox (formerly monkeypox). Identifying novel and potent antiviral...
Many poxviruses are significant human and animal pathogens, including viruses that cause smallpox and mpox (formerly monkeypox). Identifying novel and potent antiviral compounds is critical to successful drug development targeting poxviruses. Here we tested two compounds, nucleoside trifluridine, and nucleotide adefovir dipivoxil, for antiviral activities against vaccinia virus (VACV), mpox virus (MPXV), and cowpox virus (CPXV) in physiologically relevant primary human fibroblasts. Both compounds potently inhibited the replication of VACV, CPXV, and MPXV (MA001 2022 isolate) in plaque assays. In our recently developed assay based on a recombinant VACV expressing secreted Gaussia luciferase, they both exhibited high potency in inhibiting VACV replication with ECs in the low nanomolar range. In addition, both trifluridine and adefovir dipivoxil inhibited VACV DNA replication and downstream viral gene expression. Our results characterized trifluridine and adefovir dipivoxil as strong poxvirus antiviral compounds and further validate the VACV Gaussia luciferase assay as a highly efficient and reliable reporter tool for identifying poxvirus inhibitors. Given that both compounds are FDA-approved drugs, and trifluridine is already used to treat ocular vaccinia, further development of trifluridine and adefovir dipivoxil holds great promise in treating poxvirus infections, including mpox.
Topics: Animals; Humans; Vaccinia virus; Vaccinia; Cowpox virus; Antiviral Agents; Trifluridine; Mpox (monkeypox); Cell Line; Poxviridae
PubMed: 37270160
DOI: 10.1016/j.antiviral.2023.105651 -
Annals of Internal Medicine Dec 2023In their article, Edelstein and colleagues provide the results of an observational study of virologic response in patients who received treatment with...
In their article, Edelstein and colleagues provide the results of an observational study of virologic response in patients who received treatment with nirmatrelvir–ritonavir (N-R) versus those who received no COVID-19 therapy. The editorialists discuss the findings and emphasize the need for further consideration of the dosage, timing, and duration of treatment to inform optimal use of N-R.
Topics: Humans; COVID-19; Ritonavir; COVID-19 Drug Treatment; Antiviral Agents
PubMed: 37956432
DOI: 10.7326/M23-2887 -
Emerging Microbes & Infections Dec 2023Zika virus (ZIKV) infections are typically asymptomatic but cause severe neurological complications (e.g. Guillain-Barré syndrome in adults, and microcephaly in...
Zika virus (ZIKV) infections are typically asymptomatic but cause severe neurological complications (e.g. Guillain-Barré syndrome in adults, and microcephaly in newborns). There are currently no specific therapy or vaccine options available to prevent ZIKV infections. Temporal gene expression profiles of ZIKV-infected human brain microvascular endothelial cells (HBMECs) were used in this study to identify genes essential for viral replication. These genes were then used to identify novel anti-ZIKV agents and validated in publicly available data and functional wet-lab experiments. Here, we found that ZIKV effectively evaded activation of immune response-related genes and completely reprogrammed cellular transcriptional architectures. Knockdown of genes, which gradually upregulated during viral infection but showed distinct expression patterns between ZIKV- and mock infection, discovered novel proviral and antiviral factors. One-third of the 74 drugs found through signature-based drug repositioning and cross-reference with the Drug Gene Interaction Database (DGIdb) were known anti-ZIKV agents. In cellular assays, two promising antiviral candidates (Luminespib/NVP-AUY922, L-161982) were found to reduce viral replication without causing cell toxicity. Overall, our time-series transcriptome-based methods offer a novel and feasible strategy for antiviral drug discovery. Our strategies, which combine conventional and data-driven analysis, can be extended for other pathogens causing pandemics in the future.
Topics: Infant, Newborn; Humans; Zika Virus; Transcriptome; Endothelial Cells; Zika Virus Infection; Antiviral Agents; Virus Replication
PubMed: 36715162
DOI: 10.1080/22221751.2023.2174777