scholarly journals A Novel Protein Drug, Novaferon, as the Potential Antiviral Drug for COVID-19

2020 ◽  
Author(s):  
Fang Zheng ◽  
Yanwen Zhou ◽  
Zhiguo Zhou ◽  
Fei Ye ◽  
Baoying Huang ◽  
...  
Keyword(s):  
Viral Replication ◽  
Antiviral Drug ◽  
Protein Drug ◽  
Clearance Rates ◽  
Open Label ◽  
Antiviral Effects ◽  
Parallel Group ◽  
Antiviral Activities ◽  
Novel Protein

AbstractBackgroundNovaferon, a novel protein drug approved for the treatment of chronic hepatitis B in China, exhibits potent antiviral activities. We aimed to determine the anti-SARS-CoV-2 effects of Novaferon in vitro, and conducted a randomized, open-label, parallel group study to explore the antiviral effects of Novaferon for COVID-19.MethodsIn laboratory, the inhibition of Novaferon on viral replication in cells infected with SARS-CoV-2, and on SARS-CoV-2 entry into healthy cells was determined. Antiviral effects of Novaferon were evaluated in COVID-19 patients with treatment of Novaferon, Novaferon plus Lopinavir/Ritonavir, or Lopinavir/Ritonavir. The primary endpoint was the SARS-CoV-2 clearance rates on day 6 of treatment, and the secondary endpoint was the time to the SARS-CoV-2 clearance in COVID-19 patientsResultsNovaferon inhibited the viral replication in infected cells (EC50=1.02 ng/ml), and protected healthy cells from SARS-CoV-2 infection (EC50=0.1 ng/ml). Results from the 89 enrolled COVID-19 patients showed that both Novaferon and Novaferon plus Lopinavir/Ritonavir groups had significantly higher SARS-CoV-2 clearance rates on day 6 than the Lopinavir/Ritonavir group (50.0% vs.24.1%, p = 0.0400, and 60.0% vs.24.1%, p = 0.0053). Median time to SARS-CoV-2 clearance were 6 days, 6 days, and 9 days for three groups respectively, suggesting a 3-dayreduction of time to SARS-CoV-2 clearance in both Novaferon and Novaferon plus Lopinavir/Ritonavir groups compared with Lopinavir/Ritonavir group.ConclusionsNovaferon exhibited anti-SARS-CoV-2 effects in vitro and in COVID-19 patients. These data justified the further evaluation of Novaferon.

scholarly journals The Petasites hybridus CO2-extract (Ze 339) blocks SARS-CoV-2 replication in vitro

2021 ◽  
Author(s):  
Lorena Urda ◽  
Matthias Heinrich Kreuter ◽  
Jürgen Drewe ◽  
Georg Boonen ◽  
Veronika Butterweck ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Antiviral Drug ◽  
Plaque Reduction Assay ◽  
Virus Variant ◽  
Antiviral Effects ◽  
Antiviral Activities ◽  
Pre Treatment ◽  
Novel Coronavirus ◽  
Original Virus

AbstractThe coronavirus disease 2019 (COVID-19), caused by a novel coronavirus (SARS-CoV-2), has spread worldwide, affecting over 250 million people and resulting in over five million deaths. Antivirals that are effective are still limited. The antiviral activities of the Petasites hybdridus CO2-extract Ze 339 were previously reported. Thus, to assess the anti-SARS-CoV-2 activity of Ze 339 as well as isopetasin and neopetasin as major active compounds, a CPE- and plaque reduction assay in Vero E6 cells was used for viral output. Antiviral effects were tested using the original virus (Wuhan) and the Delta variant of SARS-CoV-2. The antiviral drug remdesivir was used as control. Pre-treatment with Ze 339 in SARS-CoV-2 infected Vero E6 cells with either virus variant significantly inhibited virus replication with IC50 values of 0.10 and 0.40 μg/mL, repectively. The IC50 values obtained for isopetasin ranged between 0.37-0.88 μM for both virus variants, that of remdesivir between 1.53-2.37 μM. In conclusion, Ze 339 as well as the petasins potently inhibited SARS-Cov-2 replication in vitro of the Wuhan and Delta variants. Since time is of essence in finding effective treatments, clinical studies will have to demonstrate if Ze339 can become a therapeutic option to treat SARS-CoV-2 infections.

scholarly journals Fast and scalable lipid nanoparticle formulation of niclosamide (nano NCM) effectively inhibits SARS-CoV-2 replication in vitro

2020 ◽  
Author(s):  
Guankui Wang ◽  
Hanmant Gaikwad ◽  
Mary K McCarthy ◽  
Mercedes Gonzalez-Juarrero ◽  
Yue Li ◽  
...  
Keyword(s):  
Viral Replication ◽  
Essential Medicine ◽  
Cost Effective ◽  
World Health ◽  
Lung Epithelium ◽  
Antiviral Activities ◽  
Nanoparticle Formulation ◽  
Health Organization ◽  
Epithelium Cells

As exemplified by the COVID-19 pandemic, highly infective respiratory viruses can spread rapidly in the population because of lack of effective approaches to control viral replication and spread. Niclosamide (NCM) is an old anthelminthic drug (World Health Organization essential medicine list) with pleiotropic pharmacological activities. Several recent publications demonstrated that NCM has broad antiviral activities and potently inhibits viral replication, including replication of SARS-CoV-2, SARS-CoV, and dengue viruses. Unfortunately, NCM is almost completely insoluble in water, which limits its clinical use. We developed a highly scalable and cost-effective nanoparticle formulation of NCM (nano NCM) using only FDA-approved excipient and demonstrated potency against SARS-CoV-2 infection in cells (Vero E6 and ACE2-expressing lung epithelium cells). Our ultimate goal is to develop the nano NCM formulation for treatment of COVID-19 patients.

scholarly journals Dual Inhibition of Human Rhinovirus 2A and 3C Proteases by Homophthalimides

1998 ◽  
Vol 42 (4) ◽  
pp. 916-920 ◽  
Author(s):  
Q. May Wang ◽  
Robert B. Johnson ◽  
Louis N. Jungheim ◽  
Jeffrey D. Cohen ◽  
Elcira C. Villarreal
Keyword(s):  
Antiviral Activity ◽  
Viral Replication ◽  
Enzyme Inhibitor ◽  
Antiviral Drug ◽  
3C Protease ◽  
Dependent Inhibition ◽  
Dual Inhibition ◽  
2A Protease

ABSTRACT The 2A and 3C proteases encoded by human rhinoviruses (HRVs) are attractive targets for antiviral drug development due to their important roles in viral replication. Homophthalimides were originally identified as inhibitors of rhinovirus 3C protease through our screening effort. Previous studies have indicated that the antiviral activity of certain homophthalimides exceeded their in vitro inhibitory activity against the viral 3C protease, suggesting that an additional mechanism might be involved. Reported here is the identification of homophthalimides as potent inhibitors for another rhinovirus protease, designated 2A. Several homophthalimides exhibit time-dependent inhibition of the 2A protease in the low-micromolar range, and enzyme-inhibitor complexes were identified by mass spectrometry. Compound LY343814, one of the most potent inhibitors against HRV14 2A protease, had an antiviral 50% inhibitory concentration of 4.2 μM in the cell-based assay. Our data reveal that homophthalimides are not only 3C but also 2A protease inhibitors in vitro, implying that the antiviral activity associated with these compounds might result from inactivation of both 2A and 3C proteases in vivo. Since the processing of the viral polyprotein is hierarchical, dual inhibition of the two enzymes may result in cooperative inhibition of viral replication. On the basis of the current understanding of their enzyme inhibitory mechanism, homophthalimides, as a group of novel nonpeptidic antirhinovirus agents, merit further structure-action relationship studies.

scholarly journals Spatial and temporal control of norovirus protease activity is determined by polyprotein processing and intermolecular interactions within the viral replication complex

2017 ◽  
Author(s):  
Edward Emmott ◽  
Alexis de Rougemont ◽  
Jürgen Haas ◽  
Ian Goodfellow
Keyword(s):  
Viral Replication ◽  
Protein Interactions ◽  
Full Range ◽  
Antiviral Drug ◽  
Viral Gastroenteritis ◽  
Protein Protein Interactions ◽  
Replication Complex ◽  
Viral Replication Complex ◽  
Stable Forms

AbstractNorovirus infections are a major cause of acute viral gastroenteritis and a significant burden to human health globally. A vital process for norovirus replication is the processing of the nonstructural polyprotein, by an internal protease, into the necessary viral components required to form the viral replication complex. This cleavage occurs at different rates resulting in the accumulation of stable precursor forms. In this report, we characterized how precursor forms of the norovirus protease accumulate during infection. Using stable forms of the protease precursors we demonstrated that these are all proteolytically activein vitro, but that when expressed in cells, activity is determined by both substrate and protease localization. Whilst all precursors could cleave a replication complex-associated substrate, only a subset of precursors lacking NS4 were capable of efficiently cleaving a cytoplasmic substrate. For the first time, the full range of protein-protein interactions between murine and human norovirus proteins were mapped by LUMIER assay, with conserved interactions between replication complex members, modifying the localization of a subset of precursors. Finally, we demonstrate that re-targeting of a poorly cleaved artificial cytoplasmic substrate to the replication complex is sufficient to permit efficient cleavage in the context of norovirus infection. This offers a model for how norovirus can regulate the timing of substrate cleavage throughout the replication cycle. The norovirus protease represents a key target in the search for effective antiviral treatments for norovirus infection. An improved understanding of protease function and regulation, as well as identification of interactions between the other non-structural proteins, offers new avenues for antiviral drug design.

Molecular adduct of amantadine ferulate presents a pathway for slowing in vitro/vivo releases and raising synergistic antiviral effects via dual optimization salification strategy

CrystEngComm ◽  
2021 ◽  
Author(s):  
Yuan-Yuan Niu ◽  
Ling-Yang Wang ◽  
Yue-Ming Yu ◽  
Yan-Tuan Li ◽  
Zhi-Yong Wu ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
Antiviral Effects ◽  
Molecular Adduct ◽  
Molecular Salt

The first synthesized antiviral drug-nutriment molecular salt demonstrating simultaneous slowed-release and synergistically enhanced antiviral effects is studied theoretically and experimentally.

scholarly journals Use of Cotton Rats to Evaluate the Efficacy of Antivirals in Treatment of Measles Virus Infections

2000 ◽  
Vol 44 (5) ◽  
pp. 1146-1152 ◽  
Author(s):  
Philip R. Wyde ◽  
Donna K. Moore-Poveda ◽  
Erik De Clercq ◽  
Johan Neyts ◽  
Akira Matsuda ◽  
...  
Keyword(s):  
Measles Virus ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Virus Infections ◽  
Virus Inoculation ◽  
Similar Dose ◽  
Cotton Rats ◽  
Antiviral Activities ◽  
Syncytial Virus

ABSTRACT No practical animal models for the testing of chemotherapeutic or biologic agents identified in cell culture assays as being active against measles virus (MV) are currently available. Cotton rats may serve this purpose. To evaluate this possibility, 5-ethynyl-1-β-d-ribofuranosylimidazole-4-carboxamide (EICAR) and poly(acrylamidomethyl propanesulfonate) (PAMPS), two compounds that have been reported to inhibit MV in vitro, and ribavirin, an established antiviral drug with MV-inhibitory activity, were evaluated for their antiviral activities against MV and respiratory syncytial virus (RSV) in tissue culture and in hispid cotton rats. A single administration of PAMPS markedly inhibited pulmonary RSV or MV replication (>3 log10 reduction in pulmonary titer compared to that for controls), but only if this compound was administered intranasally at about the time of virus inoculation. Both EICAR and ribavirin exhibited therapeutic activity against RSV and MV in cotton rats when they were administered parenterally. However, both of these compounds were less effective against MV. On the basis of the pulmonary virus titers on day 4 after virus inoculation, the minimal efficacious dose of EICAR against MV (120 mg/kg of body weight/day when delivered intraperitoneally twice daily) appeared to be three times lower against this virus than that of ribavirin delivered at a similar dose (i.e., 360 mg/kg/day). These findings correlated with those obtained in vitro. The data obtained suggest that cotton rats may indeed be useful for the initial evaluation of the activities of antiviral agents against MV.

scholarly journals Sophora interrupta Bedd. root-derived flavonoids as prominent antiviral agents against Newcastle disease virus

RSC Advances ◽  
2020 ◽  
Vol 10 (55) ◽  
pp. 33534-33543
Author(s):  
Cherukupalle Bhuvaneswar ◽  
Aluru Rammohan ◽  
Baki Vijaya Bhaskar ◽  
Pappithi Ramesh Babu ◽  
Gujjar Naveen ◽  
...  
Keyword(s):  
Viral Replication ◽  
Newcastle Disease Virus ◽  
Disease Virus ◽  
Newcastle Disease ◽  
Antiviral Agents ◽  
Antiviral Activities

The two flavonoids, maackiain and echinoisoflavanone from roots of Sophora interrupta Bedd. have shown prominent in vitro antiviral activities by preventing viral replication and transcription than Ribavirin against NDV in DF-1 cells.

scholarly journals Anti-Respiratory Syncytial Virus Activity of Plantago asiatica and Clerodendrum trichotomum Extracts In Vitro and In Vivo

Viruses ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 604 ◽  
Author(s):  
Kiramage Chathuranga ◽  
Myun Soo Kim ◽  
Hyun-Cheol Lee ◽  
Tae-Hwan Kim ◽  
Jae-Hoon Kim ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Antiviral Drug ◽  
A549 Cells ◽  
Phenolic Glycoside ◽  
Antiviral Effects ◽  
Plantago Asiatica ◽  
Syncytial Virus ◽  
Herb Extract

The herbs Plantago asiatica and Clerodendrum trichotomum have been commonly used for centuries in indigenous and folk medicine in tropical and subtropical regions of the world. In this study, we show that extracts from these herbs have antiviral effects against the respiratory syncytial virus (RSV) in vitro cell cultures and an in vivo mouse model. Treatment of HEp2 cells and A549 cells with a non-cytotoxic concentration of Plantago asiatica or Clerodendrum trichotomum extract significantly reduced RSV replication, RSV-induced cell death, RSV gene transcription, RSV protein synthesis, and also blocked syncytia formation. Interestingly, oral inoculation with each herb extract significantly improved viral clearance in the lungs of BALB/c mice. Based on reported information and a high-performance liquid chromatography (HPLC) analysis, the phenolic glycoside acteoside was identified as an active chemical component of both herb extracts. An effective dose of acteoside exhibited similar antiviral effects as each herb extract against RSV in vitro and in vivo. Collectively, these results suggest that extracts of Plantago asiatica and Clerodendrum trichotomum could provide a potent natural source of an antiviral drug candidate against RSV infection.

scholarly journals Interaction of Ritonavir-Boosted Tipranavir with Loperamide Does Not Result in Loperamide-Associated Neurologic Side Effects in Healthy Volunteers

2005 ◽  
Vol 49 (12) ◽  
pp. 4903-4910 ◽  
Author(s):  
Geoffrey Mukwaya ◽  
Thomas MacGregor ◽  
David Hoelscher ◽  
Thomas Heming ◽  
Daniel Legg ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Respiratory Depression ◽  
Pupillary Response ◽  
Response Curves ◽  
Open Label ◽  
Healthy Human ◽  
Time Curve ◽  
Parallel Group

ABSTRACT Loperamide (LOP) is a peripherally acting opioid receptor agonist used for the management of chronic diarrhea through the reduction of gut motility. The lack of central opioid effects is partly due to the efflux activity of the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier. The protease inhibitors are substrates for P-gp and have the potential to cause increased LOP levels in the brain. Because protease inhibitors, including tipranavir (TPV), are often associated with diarrhea, they are commonly used in combination with LOP. The level of respiratory depression, the level of pupil constriction, the pharmacokinetics, and the safety of LOP alone compared with those of LOP-ritonavir (RTV), LOP-TPV, and LOP-TPV-RTV were evaluated in a randomized, open-label, parallel-group study with 24 healthy human immunodeficiency virus type 1-negative adults. Respiratory depression was assessed by determination of the ventilatory response to carbon dioxide. Tipranavir-containing regimens (LOP-TPV and LOP-TPV-RTV) caused decreases in the area under the concentration-time curve from time zero to infinity for LOP (51% and 63% decreases, respectively) and its metabolite (72% and 77% decreases, respectively), whereas RTV caused increases in the levels of exposure of LOP (121% increase) and its metabolite (44% increase). In vitro and in vivo data suggest that TPV is a substrate for and an inducer of P-gp activity. The respiratory response to LOP in combination with TPV and/or RTV was not different from that to LOP alone. There was no evidence that LOP had opioid effects in the central nervous system, as measured indirectly by CO2 response curves and pupillary response in the presence of TPV and/or RTV.

scholarly journals Impact of the rtI187V polymerase substitution of hepatitis B virus on viral replication and antiviral drug susceptibility

2014 ◽  
Vol 95 (11) ◽  
pp. 2523-2530 ◽  
Author(s):  
Jiyun Fan ◽  
Ying Wang ◽  
Hui Xiong ◽  
Xiaokui Guo ◽  
Yung-chi Cheng
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Viral Replication ◽  
Antiviral Drug ◽  
Drug Susceptibility ◽  
Hbv Genotype ◽  
B Virus ◽  
High Prevalence ◽  
Chinese Cohort

A high prevalence of the rtI187V polymerase substitution of hepatitis B virus (HBV) was detected in nucleoside/nucleotide-analogue-naive and -treated chronic hepatitis B (CHB) patients. We aimed at assessing the replicative capacity and susceptibility to lamivudine (LAM) and adefovir (ADV) in vitro of HBV harbouring rtI187V alone or in conjunction with LAM- or ADV-resistant mutations. The reverse transcriptase region of HBV isolates was directly sequenced from a cohort of 300 CHB patients from China. Replication-competent HBV constructs containing rtI187V and combined with LAM-resistant (rtM204I, rtL180M/rtM204V) mutations were generated, and compared with WT, LAM-resistant single (rtM204I) or double (rtL180M/rtM204V) and ADV-resistant (rtN236T) clones. In a Chinese cohort of 300 CHB patients, 8.7 % (26/300) showed substitution of rtI187 with V. Of note, the rtI187V prevalence in HBV genotype B was significantly higher than that in HBV genotype C (95.2 vs 4.8 %). In vitro phenotypic assays showed that the viruses bearing the rtI187V substitution had impaired replication efficacy when compared with the WT and the virus carrying rtI187V combined with LAM-resistant single or double mutations showed even more significantly impaired replicative capacities. Furthermore, rtI187V HBV remained susceptible towards treatment with LAM or ADV in vitro whereas the combination of the rtI187V substitution with LAM-resistant mutations rendered HBV resistant to LAM but still sensitive to ADV. Our study revealed that the rtI187V substitution in the HBV polymerase frequently occurred in CHB patients, particularly those with HBV genotype B. However, the emergence of the rtI187V substitution significantly impaired viral replication but without affecting drug sensitivity in vitro.

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