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Clinical Infectious Diseases : An... Aug 2021
Topics: Amides; Antiviral Agents; COVID-19; Humans; Pyrazines; SARS-CoV-2
PubMed: 33075124
DOI: 10.1093/cid/ciaa1600 -
Expert Review of Pharmacoeconomics &... 2015In the USA, over 3 million individuals are infected with the HCV and 75-85% of them have or will develop chronic hepatitis C (CHC) which can lead to serious consequences... (Review)
Review
In the USA, over 3 million individuals are infected with the HCV and 75-85% of them have or will develop chronic hepatitis C (CHC) which can lead to serious consequences such as liver cirrhosis, cancer and death. The old standard of care for the treatment of CHC was Pegylated-Interferon + Ribavirin with or without a protease inhibitor such as Boceprevir/Telaprevir. These treatments had a cure rate or rate of sustained virologic response of 66-80%. Since the close of 2013, several new direct acting antiviral agents (DAAs) for the treatment of CHC have been approved by the US FDA and have entered the US drug market. These novel CHC treatments boast very high cure rates of 80-100% and come with matching high price tags. Costs of CHC regimens that contain these novel DAAs range from $63,000 to $168,000 per treatment course. Using electronic databases, studies evaluating the cost-effectiveness of novel CHC treatments in USA were reviewed, and the reported incremental cost-effectiveness ratios based on cost per additional quality adjusted life year gained from the studies reviewed indicated that some novel DAA regimens are cost-effective; however, cost-effectiveness is contingent upon a variety of factors such as HCV genotype (1-4), presence of liver cirrhosis, patient treatment history and willingness-to-pay thresholds.
Topics: Antiviral Agents; Cost-Benefit Analysis; Drug Approval; Drug Design; Hepacivirus; Hepatitis C, Chronic; Humans; Quality-Adjusted Life Years; United States; United States Food and Drug Administration
PubMed: 26289734
DOI: 10.1586/14737167.2015.1076337 -
Chemical Biology & Drug Design Jun 2022Nucleoside analogs are the backbone of antiviral therapies. Drugs from this class undergo processing by host or viral kinases to form the active nucleoside triphosphate...
Nucleoside analogs are the backbone of antiviral therapies. Drugs from this class undergo processing by host or viral kinases to form the active nucleoside triphosphate species that selectively inhibits the viral polymerase. It is the central hypothesis that the nucleoside triphosphate analog must be a favorable substrate for the viral polymerase and the nucleoside precursor must be a satisfactory substrate for the host kinases to inhibit viral replication. Herein, free energy perturbation (FEP) was used to predict substrate affinity for both host and viral enzymes. Several uridine 5'-monophosphate prodrug analogs known to inhibit hepatitis C virus (HCV) were utilized in this study to validate the use of FEP. Binding free energies to the host monophosphate kinase and viral RNA-dependent RNA polymerase (RdRp) were calculated for methyl-substituted uridine analogs. The 2'-C-methyl-uridine and 4'-C-methyl-uridine scaffolds delivered favorable substrate binding to the host kinase and HCV RdRp that were consistent with results from cellular antiviral activity in support of our new approach. In a prospective evaluation, FEP results suggest that 2'-C-dimethyl-uridine scaffold delivered favorable monophosphate and triphosphate substrates for both host kinase and HCV RdRp, respectively. Novel 2'-C-dimethyl-uridine monophosphate prodrug was synthesized and exhibited sub-micromolar inhibition of HCV replication. Using this novel approach, we demonstrated for the first time that nucleoside analogs can be rationally designed that meet the multi-target requirements for antiviral activity.
Topics: Antiviral Agents; Hepacivirus; Hepatitis C; Humans; Nucleosides; Nucleotides; Prodrugs; RNA-Dependent RNA Polymerase; Uridine; Viral Nonstructural Proteins; Virus Replication
PubMed: 35313085
DOI: 10.1111/cbdd.14042 -
Medicinal Research Reviews Jul 2015Antiviral drug development has often followed a curious meandrous route, guided by serendipity rather than rationality. This will be illustrated by ten examples. The... (Review)
Review
Antiviral drug development has often followed a curious meandrous route, guided by serendipity rather than rationality. This will be illustrated by ten examples. The polyanionic compounds (i) polyethylene alanine (PEA) and (ii) suramin were designed as an antiviral agent (PEA) or known as an antitrypanosomal agent (suramin), before they emerged as, respectively, a depilatory agent, or reverse transcriptase inhibitor. The 2',3'-dideoxynucleosides (ddNs analogues) (iii) have been (and are still) used in the "Sanger" DNA sequencing technique, although they are now commercialized as nucleoside reverse transcriptase inhibitors (NRTIs) in the treatment of HIV infections. (E)-5-(2-Bromovinyl)-2'-deoxyuridine (iv) was discovered as a selective anti-herpes simplex virus compound and is now primarily used for the treatment of varicella-zoster virus infections. The prototype of the acyclic nucleoside phosphonates (ANPs), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], (v) was never commercialized, although it gave rise to several marketed products (cidofovir, adefovir, and tenofovir). 1-[2-(Hydroxyethoxy)methyl]-6-(phenylthio)thymine (vi) and TIBO (tetrahydroimidazo[4,5,1-jk][1,4-benzodiazepin-2(1H)]-one and -thione) (vii) paved the way to a number of compounds (i.e., nevirapine, delavirdine, etravirine, and rilpivirine), which are now collectively called non-NRTIs. The bicyclam AMD3100 (viii) was originally described as an anti-HIV agent before it became later marketed as a stem cell mobilizer. The S-adenosylhomocysteine hydrolase inhibitors (ix), while active against a broad range of (-)RNA viruses and poxviruses may be particularly effective against Ebola virus, and for (x) the O-ANP derivatives, the potential application range encompasses virtually all DNA viruses.
Topics: Animals; Antiviral Agents; Drug Discovery; Enzyme Inhibitors; Humans
PubMed: 25726922
DOI: 10.1002/med.21340 -
Future Medicinal Chemistry May 2022In the last two decades, the world has witnessed the emergence of zoonotic corona viruses (CoVs), which cause mild to severe respiratory diseases in humans. Human...
In the last two decades, the world has witnessed the emergence of zoonotic corona viruses (CoVs), which cause mild to severe respiratory diseases in humans. Human coronaviruses (HCoVs), mainly from the alpha-CoV and beta-CoV genera, have evolved to be highly pathogenic, such as SARS-CoV-2 causing the COVID-19 pandemic. These coronaviruses carry functional enzymes necessary for the virus life cycle, which represent attractive antiviral targets. We aimed to therapeutically target the main protease (Mpro) of HCoV-NL63 and HCoV-229E (from alpha-CoV genus) and HCoV-OC43 and SARS-CoV-2 (from beta-CoV genus). Through virtual screening, we identified an FDA-approved drug dyphylline, a xanthine derivate, that binds to the catalytic dyad residues; histidine and cystine of the Mpro structures. Importantly, dyphylline dose-dependently inhibited the viral replication in cell culture models infected with the viruses. Our findings support the repurposing of dyphylline as a pan-coronavirus antiviral agent.
Topics: Antiviral Agents; Drug Repositioning; Dyphylline; Humans; Pandemics; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35387498
DOI: 10.4155/fmc-2021-0311 -
Proceedings of the National Academy of... Jun 1998A dynamic capsid is critical to the events that shape the viral life cycle; events such as cell attachment, cell entry, and nucleic acid release demand a highly mobile...
A dynamic capsid is critical to the events that shape the viral life cycle; events such as cell attachment, cell entry, and nucleic acid release demand a highly mobile viral surface. Protein mass mapping of the common cold virus, human rhinovirus 14 (HRV14), revealed both viral structural dynamics and the inhibition of such dynamics with an antiviral agent, WIN 52084. Viral capsid digestion fragments resulting from proteolytic time-course experiments provided structural information in good agreement with the HRV14 three-dimensional crystal structure. As expected, initial digestion fragments included peptides from the capsid protein VP1. This observation was expected because VP1 is the most external viral protein. Initial digestion fragments also included peptides belonging to VP4, the most internal capsid protein. The mass spectral results together with x-ray crystallography data provide information consistent with a "breathing" model of the viral capsid. Whereas the crystal structure of HRV14 shows VP4 to be the most internal capsid protein, mass spectral results show VP4 fragments to be among the first digestion fragments observed. Taken together this information demonstrates that VP4 is transiently exposed to the viral surface via viral breathing. Comparative digests of HRV14 in the presence and absence of WIN 52084 revealed a dramatic inhibition of digestion. These results indicate that the binding of the antiviral agent not only causes local conformational changes in the drug binding pocket but actually stabilizes the entire viral capsid against enzymatic degradation. Viral capsid mass mapping provides a fast and sensitive method for probing viral structural dynamics as well as providing a means for investigating antiviral drug efficacy.
Topics: Antiviral Agents; Humans; Isoxazoles; Protein Conformation; Rhinovirus; Viral Proteins; Virus Assembly
PubMed: 9618488
DOI: 10.1073/pnas.95.12.6774 -
Drug Intelligence & Clinical Pharmacy May 1987Remarkable progress has been made in antiviral chemotherapy. Six approved antiviral drugs are now available for the treatment of various viral infections. Trifluridine,... (Review)
Review
Remarkable progress has been made in antiviral chemotherapy. Six approved antiviral drugs are now available for the treatment of various viral infections. Trifluridine, idoxuridine and vidarabine are all effective in patients with herpes keratitis; trifluridine is preferred due to its low toxicity. Acyclovir is the drug of choice in patients with infections due to herpes simplex viruses, including genital herpes, herpes encephalitis, and neonatal herpes, and infections due to varicella-zoster virus. Amantadine is the only drug currently available for prophylaxis and treatment of influenza A, but an investigational drug, rimantadine, appears to be equally effective and less toxic than amantadine. Ribavirin is the most recently approved antiviral agent for the treatment of respiratory syncytial virus infections. Numerous antiviral drugs are being studied in patients with acquired immunodeficiency syndrome. Although currently available drugs have improved our ability to manage a variety of viral illnesses, much needs to be learned about specific dosage guidelines based on the studies of pharmacokinetics, pharmacodynamics, potential adverse effects and viral resistance, and the role of combination therapy to optimize therapy.
Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Antiviral Agents; Child; Humans; Infant, Newborn; Middle Aged; Ribavirin; Virus Diseases
PubMed: 3556126
DOI: 10.1177/106002808702100501 -
Journal of Periodontology Jul 2022It is well recognized that dental procedures represent a potential way of infection transmission. With the COVID-19 pandemic, the focus of dental procedure associated...
BACKGROUND
It is well recognized that dental procedures represent a potential way of infection transmission. With the COVID-19 pandemic, the focus of dental procedure associated transmission has rapidly changed from bacteria to viruses. The aim was to develop an experimental setup for testing the spread of viruses by ultrasonic scaler (USS) generated dental spray and evaluate its mitigation by antiviral coolants.
METHODS
In a virus transmission tunnel, the dental spray was generated by USS with saline coolant and suspension of Equine Arteritis Virus (EAV) delivered to the USS tip. Virus transmission by settled droplets was evaluated with adherent RK13 cell lines culture monolayer. The suspended droplets were collected by a cyclone aero-sampler. Antiviral activity of 0.25% NaOCl and electrolyzed oxidizing water (EOW) was tested using a suspension test. Antiviral agents' transmission prevention ability was evaluated by using them as a coolant.
RESULTS
In the suspension test with 0.25% NaOCl or EOW, the TCID50/mL was below the detection limit after 5 seconds. With saline coolant, the EAV-induced cytopathic effect on RK13 cells was found up to the distance of 45 cm, with the number of infected cells decreasing with distance. By aero-sampler, viral particles were detected in concentration ≤4.2 TCID50/mL. With both antiviral agents used as coolants, no EAV-associated RK-13 cell infection was found.
CONCLUSION
We managed to predictably demonstrate EAV spread by droplets because of USS action. More importantly, we managed to mitigate the spread by a simple substitution of the USS coolant with NaOCl or EOW.
Topics: Animals; Antiviral Agents; COVID-19; Equartevirus; Horses; Humans; Pandemics; Ultrasonics
PubMed: 34730843
DOI: 10.1002/JPER.21-0335 -
Antiviral Research Sep 2023We employed an advanced virtual screening (AVS) approach to identify potential inhibitors of human dihydroorotate dehydrogenase (DHODH), a validated target for...
We employed an advanced virtual screening (AVS) approach to identify potential inhibitors of human dihydroorotate dehydrogenase (DHODH), a validated target for development of broad-spectrum antivirals. We screened a library of 495118 compounds and identified 495 compounds that exhibited better binding scores than the reference ligands involved in the screening. From the top 100 compounds, we selected 28 based on their consensus docking scores and structural novelty. Then, we conducted in vitro experiments to investigate the antiviral activity of selected compounds on HSV-1 infection, which is susceptible to DHODH inhibitors. Among the tested compounds, seven displayed statistically significant antiviral effects, with Comp 19 being the most potent inhibitor. We found that Comp 19 exerted its antiviral effect in a dose-dependent manner (IC = 1.1 μM) and exhibited the most significant antiviral effect when added before viral infection. In the biochemical assay, Comp 19 inhibited human DHODH in a dose-dependent manner with the IC value of 7.3 μM. Long-timescale molecular dynamics simulations (1000 ns) revealed that Comp 19 formed a very stable complex with human DHODH. Comp 19 also displayed broad-spectrum antiviral activity and suppressed cytokine production in THP-1 cells. Overall, our study provides evidence that AVS could be successfully implemented to discover novel DHODH inhibitors with broad-spectrum antiviral activity.
Topics: Humans; Antiviral Agents; Dihydroorotate Dehydrogenase; Oxidoreductases Acting on CH-CH Group Donors; Enzyme Inhibitors
PubMed: 37499699
DOI: 10.1016/j.antiviral.2023.105681 -
Broad Antiviral Spectrum of Glycyrrhizic Acid for Human and Veterinary Medicine: Reality or Fiction?Intervirology 2023Emerging virus infections provoke health problems in people and animals, which generate social and economic issues worldwide. This has spurred the search for new... (Review)
Review
BACKGROUND
Emerging virus infections provoke health problems in people and animals, which generate social and economic issues worldwide. This has spurred the search for new pharmacological strategies to confront them.
SUMMARY
The purpose of this review is to draw the reader's attention to pharmacological evaluations of glycyrrhizic acid (GA) and its analogs on the broad range of viruses known in human and veterinary medicine. GA is the main water-soluble constituent extracted from the roots of plants from the genus Glycyrrhiza, commonly known as licorice root. It has long been used due to its broad spectrum of bioactivities, including anti-inflammatory, antiulcer, and antitumor properties. It has also been proposed as an antiviral agent. Medicines derived from GA are currently being used to combat acute and chronic hepatitis and herpes viruses.
KEY MESSAGES
This review suggests that GA could be a new broad-spectrum antiviral due to its ability to inhibit DNA or RNA viruses both in vitro and in vivo. GA could be a potential drug for preventing and/or treating various viral diseases.
Topics: Animals; Humans; Glycyrrhizic Acid; Antiviral Agents; Viruses; Virus Diseases; Water
PubMed: 36455522
DOI: 10.1159/000528198