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Antimicrobial Agents and Chemotherapy Oct 2022Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed... (Randomized Controlled Trial)
Randomized Controlled Trial
Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1, = 50) and multiple (part 2, = 33) ascending oral doses. Effect of food on the pharmacokinetics of ensitrelvir, differences in pharmacokinetics of ensitrelvir between Japanese and white participants, and effect of ensitrelvir on the pharmacokinetics of midazolam (a cytochrome P450 3A [CYP3A] substrate) were also assessed. In part 1, Japanese participants were randomized to placebo or ensitrelvir at doses of 20, 70, 250, 500, 1,000, or 2,000 mg. In part 2, Japanese and white participants were randomized to placebo or once-daily ensitrelvir at loading/maintenance dose 375/125 mg or 750/250 mg for 5 days. Most treatment-related adverse events observed were mild in severity and were resolved without treatment. Plasma exposures showed almost dose proportionality, and geometric mean half-life of ensitrelvir following the single dose was 42.2 to 48.1 h. Food intake reduced and delayed of ensitrelvir but did not impact the area under the curve (AUC), suggesting suitability for administration without food restriction. Compared with Japanese participants, plasma exposures were slightly lower for white participants. Ensitrelvir affected the pharmacokinetics of CYP3A substrates because of increase in AUC of midazolam coadministered with ensitrelvir 750/250 mg on day 6. In conclusion, ensitrelvir was well-tolerated and demonstrated favorable pharmacokinetics, including a long half-life, supporting once-daily oral dosing. These results validate further assessments of ensitrelvir in participants with SARS-CoV-2 infection.
Topics: Adult; Humans; Administration, Oral; Antiviral Agents; Area Under Curve; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Healthy Volunteers; Midazolam; Peptide Hydrolases; Protease Inhibitors; SARS-CoV-2; Indazoles; Triazines; Triazoles; COVID-19 Drug Treatment
PubMed: 36094202
DOI: 10.1128/aac.00632-22 -
Biochemical and Biophysical Research... Jan 2021FDA approved for parasitic indications, the small molecule ivermectin has been the focus of growing attention in the last 8 years due to its potential as an antiviral.... (Review)
Review
FDA approved for parasitic indications, the small molecule ivermectin has been the focus of growing attention in the last 8 years due to its potential as an antiviral. We first identified ivermectin in a high throughput compound library screen as an agent potently able to inhibit recognition of the nuclear localizing Human Immunodeficiency Virus-1 (HIV-1) integrase protein by the host importin (IMP) α/β1 heterodimer, and recently demonstrated its ability to bind directly to IMPα to cause conformational changes that prevent its function in nuclear import of key viral as well as host proteins. Cell culture experiments have shown robust antiviral action towards a whole range of viruses, including HIV-1, dengue, Zika and West Nile Virus, Venezuelan equine encephalitis virus, Chikungunya, pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19). Close to 70 clinical trials are currently in progress worldwide for SARS-CoV-2. Although few of these studies have been completed, the results that are available, as well as those from observational/retrospective studies, indicate clinical benefit. Here we discuss the case for ivermectin as a host-directed broad-spectrum antiviral agent, including for SARS-CoV-2.
Topics: Antiparasitic Agents; Antiviral Agents; Humans; Ivermectin; SARS-CoV-2; alpha Karyopherins; COVID-19 Drug Treatment
PubMed: 33341233
DOI: 10.1016/j.bbrc.2020.10.042 -
Molecular Biology Reports Oct 2020COVID-19 caused by the SARS-CoV-2 outbreak quickly has turned into a pandemic. However, no specific antiviral agent is yet available. In this communication, we aimed to... (Review)
Review
COVID-19 caused by the SARS-CoV-2 outbreak quickly has turned into a pandemic. However, no specific antiviral agent is yet available. In this communication, we aimed to evaluate the significance of CD147 protein and the potential protective effect of melatonin that is mediated by this protein in COVID-19. CD147 is a glycoprotein that is responsible for the cytokine storm in the lungs through the mediation of viral invasion. Melatonin use previously was shown to reduce cardiac damage by blocking the CD147 activity. Hence, melatonin, a safe drug, may prevent severe symptoms, reduce symptom severity and the adverse effects of the other antiviral drugs in COVID-19 patients. In conclusion, the use of melatonin, which is reduced in the elderly and immune-compromised patients, should be considered as an adjuvant through its CD147 suppressor and immunomodulatory effect.
Topics: Adjuvants, Pharmaceutic; Animals; Antioxidants; Antiviral Agents; Basigin; COVID-19; Coronavirus Infections; Humans; Immune System; Melatonin; Pandemics; Pneumonia, Viral; Signal Transduction
PubMed: 32920757
DOI: 10.1007/s11033-020-05830-8 -
Carbohydrate Polymers Sep 2022As a significant public health hazard with several drug side effects during medical treatment, searching for novel therapeutic natural medicines is promising. Sulfated... (Review)
Review
As a significant public health hazard with several drug side effects during medical treatment, searching for novel therapeutic natural medicines is promising. Sulfated polysaccharides from algae, such as fucoidan, have been discovered to have a variety of medical applications, including antibacterial and immunomodulatory properties. The review emphasized on the utilization of fucoidan as an antiviral agent against viral infections by inhibiting their attachment and replication. Moreover, it can also trigger immune response against viral infection in humans. This review suggested to be use the fucoidan for the potential protective remedy against COVID-19 and addressing the antiviral activities of sulfated polysaccharide, fucoidan derived from marine algae that could be used as an anti-COVID19 drug in near future.
Topics: Antiviral Agents; Humans; Polysaccharides; Sulfates; COVID-19 Drug Treatment
PubMed: 35698330
DOI: 10.1016/j.carbpol.2022.119551 -
Canadian Journal of Gastroenterology &... Sep 2014Between 2001 and 2011, the standard of care for chronic hepatitis C virus (HCV) infection was a combination of pegylated interferon (PEG-IFN) and ribavirin (RBV). In May... (Review)
Review
Between 2001 and 2011, the standard of care for chronic hepatitis C virus (HCV) infection was a combination of pegylated interferon (PEG-IFN) and ribavirin (RBV). In May 2011, boceprevir and telaprevir, two first-generation NS3/4A protease inhibitors, were approved in combination with PEG-IFN and RBV for 24 to 48 weeks in hepatitis C virus genotype 1 infections. In December 2013, simeprevir, a second-generation NS3/4A protease inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotype 1, while sofosbuvir, a NS5B nucleotide polymerase inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotypes 1 and 4, as well as with RBV alone for 12 weeks in genotype 2 and for 24 weeks in genotype 3. Sofosbuvir combined with simeprevir or an NS5A replication complex inhibitor (ledipasvir or daclatasvir) with or without RBV for 12 weeks in genotype 1 resulted in a sustained virological response >90%, irrespective of previous treatment history or presence of cirrhosis. Similarly impressive sustained virological response rates have been shown with ABT-450/r (ritonavir-boosted NS3/4A protease inhibitor)-based regimens in combination with other direct-acting antiviral agent(s) with or without RBV for 12 weeks in genotype 1. The optimal all-oral interferon-free antiviral regimen likely entails a combination of an NS5B nucleotide polymerase inhibitor with either a second-generation NS3/4A protease inhibitor or an NS5A replication complex inhibitor with or without RBV. Further research is needed to determine the role of resistance testing, clarify the optimal follow-up duration post-treatment, and evaluate the antiviral efficacy and safety in difficult-to-cure patient populations.
Topics: Administration, Oral; Antiviral Agents; Drug Approval; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Ribavirin
PubMed: 25229466
DOI: 10.1155/2014/549624 -
Antiviral Chemistry & Chemotherapy Sep 2012Ribavirin has been used as an antiviral agent for several decades. Although it has activity against numerous viruses, its major use clinically has been in the treatment... (Review)
Review
Ribavirin has been used as an antiviral agent for several decades. Although it has activity against numerous viruses, its major use clinically has been in the treatment of respiratory syncytial virus in paediatric patients and chronic HCV infection in both children and adults. This review highlights the clinical application and mechanism of action of ribavirin and discusses the future role of ribavirin in treatment of HCV where there are intense research efforts to improve therapy.
Topics: Animals; Antiviral Agents; Hepatitis C; Humans; Ribavirin
PubMed: 22592135
DOI: 10.3851/IMP2125 -
Molecules (Basel, Switzerland) Dec 2020Curcumin is a natural compound that has many medical applications. However, its low solubility and poor stability could impede its clinical applications. The present...
Development of Provesicular Nanodelivery System of Curcumin as a Safe and Effective Antiviral Agent: Statistical Optimization, In Vitro Characterization, and Antiviral Effectiveness.
Curcumin is a natural compound that has many medical applications. However, its low solubility and poor stability could impede its clinical applications. The present study aimed to formulate dry proniosomes to overcome these pitfalls and improve the therapeutic efficacy of Curcumin. Curcumin-loaded proniosomes were fabricated by the slurry method according to 3 factorial design using Design-Expert software to demonstrate the impact of different independent variables on entrapment efficiency (EE%) and % drug released after 12 h (Q). The optimized formula (F5) was selected according to the desirability criteria. F5 exhibited good flowability and appeared, after reconstitution, as spherical nanovesicles with EE% of 89.94 ± 2.31% and Q of 70.89 ± 1.62%. F5 demonstrated higher stability and a significant enhancement of Q than the corresponding niosomes. The docking study investigated the ability of Curcumin to bind effectively with the active site of DNA polymerase of Herpes simplex virus (HSV). The antiviral activity and the safety of F5 were significantly higher than Curcumin. F5 improved the safety of Acyclovir (ACV) and reduced its effective dose that produced a 100% reduction of viral plaques. Proniosomes could be promising stable carriers of Curcumin to be used as a safe and efficient antiviral agent.
Topics: Animals; Antineoplastic Agents; Antiviral Agents; Chlorocebus aethiops; Curcumin; Drug Delivery Systems; Herpes Simplex; In Vitro Techniques; Liposomes; Nanoparticles; Simplexvirus; Vero Cells
PubMed: 33271831
DOI: 10.3390/molecules25235668 -
PloS One 2022Potent broad-spectrum antiviral agents are urgently needed to combat existing and emerging viral infections. This is particularly important considering that vaccine...
Potent broad-spectrum antiviral agents are urgently needed to combat existing and emerging viral infections. This is particularly important considering that vaccine development is a costly and time consuming process and that viruses constantly mutate and render the vaccine ineffective. Antimicrobial peptides (AMP), such as bacteriocins, are attractive candidates as antiviral agents against enveloped viruses. One of these bacteriocins is PLNC8 αβ, which consists of amphipathic peptides with positive net charges that display high affinity for negatively charged pathogen membrane structures, including phosphatidylserine rich lipid membranes of viral envelopes. Due to the morphological and physiological differences between viral envelopes and host cell plasma membranes, PLNC8 αβ is thought to have high safety profile by specifically targeting viral envelopes without effecting host cell membranes. In this study, we have tested the antiviral effects of PLNC8 αβ against the flaviviruses Langat and Kunjin, coronavirus SARS-CoV-2, influenza A virus (IAV), and human immunodeficiency virus-1 (HIV-1). The concentration of PLNC8 αβ that is required to eliminate all the infective virus particles is in the range of nanomolar (nM) to micromolar (μM), which is surprisingly efficient considering the high content of cholesterol (8-35%) in their lipid envelopes. We found that viruses replicating in the endoplasmic reticulum (ER)/Golgi complex, e.g. SARS-CoV-2 and flaviviruses, are considerably more susceptible to PLNC8 αβ, compared to viruses that acquire their lipid envelope from the plasma membrane, such as IAV and HIV-1. Development of novel broad-spectrum antiviral agents can significantly benefit human health by rapidly and efficiently eliminating infectious virions and thereby limit virus dissemination and spreading between individuals. PLNC8 αβ can potentially be developed into an effective and safe antiviral agent that targets the lipid compartments of viral envelopes of extracellular virions, more or less independent of virus antigenic mutations, which faces many antiviral drugs and vaccines.
Topics: Humans; Antiviral Agents; Bacteriocins; COVID-19; Encephalitis Viruses, Tick-Borne; HIV-1; Influenza A virus; Lipids; SARS-CoV-2
PubMed: 36449554
DOI: 10.1371/journal.pone.0278419 -
PLoS Pathogens Feb 2022Viral infection of the heart is a common but underappreciated cause of heart failure. Viruses can cause direct cardiac damage by lysing infected cardiomyocytes....
Viral infection of the heart is a common but underappreciated cause of heart failure. Viruses can cause direct cardiac damage by lysing infected cardiomyocytes. Inflammatory immune responses that limit viral replication can also indirectly cause damage during infection, making regulatory factors that fine-tune these responses particularly important. Identifying and understanding these factors that regulate cardiac immune responses during infection will be essential for developing targeted treatments for virus-associated heart failure. Our laboratory has discovered Brain Expressed X-linked protein 1 (BEX1) as a novel stress-regulated pro-inflammatory factor in the heart. Here we report that BEX1 plays a cardioprotective role in the heart during viral infection. Specifically, we adopted genetic gain- and loss-of-function strategies to modulate BEX1 expression in the heart in the context of coxsackievirus B3 (CVB3)-induced cardiomyopathy and found that BEX1 limits viral replication in cardiomyocytes. Interestingly, despite the greater viral load observed in mice lacking BEX1, inflammatory immune cell recruitment in the mouse heart was profoundly impaired in the absence of BEX1. Overall, the absence of BEX1 accelerated CVB3-driven heart failure and pathologic heart remodeling. This result suggests that limiting inflammatory cell recruitment has detrimental consequences for the heart during viral infections. Conversely, transgenic mice overexpressing BEX1 in cardiomyocytes revealed the efficacy of BEX1 for counteracting viral replication in the heart in vivo. We also found that BEX1 retains its antiviral role in isolated cells. Indeed, BEX1 was necessary and sufficient to counteract viral replication in both isolated primary cardiomyocytes and mouse embryonic fibroblasts suggesting a broader applicability of BEX1 as antiviral agent that extended to viruses other than CVB3, including Influenza A and Sendai virus. Mechanistically, BEX1 regulated interferon beta (IFN-β) expression in infected cells. Overall, our study suggests a multifaceted role of BEX1 in the cardiac antiviral immune response.
Topics: Animals; Antiviral Agents; Coxsackievirus Infections; Enterovirus B, Human; Fibroblasts; Heart Failure; Mice; Myocarditis; Myocytes, Cardiac; Virus Diseases; Virus Replication
PubMed: 35192678
DOI: 10.1371/journal.ppat.1010342 -
Nucleosides, Nucleotides & Nucleic Acids Jan 2017A novel series of tetrafluoro and hexafluoro acyclic nucleosides and their phosphoramidates were successfully prepared from commercially available...
A novel series of tetrafluoro and hexafluoro acyclic nucleosides and their phosphoramidates were successfully prepared from commercially available 2,2,3,3-tetrafluoro-1,4-butanediol and 2,2,3,3,4,4-hexafluoro-1,5-pentanediol in four to six steps. Their ability to block HIV, HCV, HSV-1, and HBV replication along with their cytotoxicity toward HepG2, human lymphocyte, CEM, and Vero cells was assessed.
Topics: Amides; Animals; Anti-HIV Agents; Antiviral Agents; Chemistry Techniques, Synthetic; Drug Evaluation, Preclinical; Fluorine; Hep G2 Cells; Hepatitis B virus; Herpesvirus 1, Human; Humans; Molecular Structure; Nucleosides; Phosphoric Acids; Vero Cells; Virus Replication
PubMed: 27759481
DOI: 10.1080/15257770.2016.1218023