scholarly journals The in vitro and in vivo potency of CT-P59 against Delta and its associated variants of SARS-CoV-2

2021 ◽  
Author(s):  
Dong-Kyun Ryu ◽  
Hye-Min Woo ◽  
Bobin Kang ◽  
Hanmi Noh ◽  
Jong-In Kim ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Respiratory Tract ◽  
Animal Studies ◽  
Antiviral Effect ◽  
The World ◽  
Symptom Remission ◽  
Challenge Experiment ◽  
Reduced Activity

The Delta variant originally from India is rapidly spreading across the world and causes to resurge infections of SARS-CoV-2. We previously reported that CT-P59 presented its in vivo potency against Beta and Gamma variants, despite its reduced activity in cell experiments. Yet, it remains uncertain to exert the antiviral effect of CT-P59 on the Delta and its associated variants (L452R). To tackle this question, we carried out cell tests and animal study. CT-P59 showed reduced antiviral activity but enabled neutralization against Delta, Epsilon, and Kappa variants in cells. In line with in vitro results, the mouse challenge experiment with the Delta variant substantiated in vivo potency of CT-P59 showing symptom remission and virus abrogation in the respiratory tract. Collectively, cell and animal studies showed that CT-P59 is effective against the Delta variant infection, hinting that CT-P59 has therapeutic potency for patients infected with Delta and its associated variants.

scholarly journals Nafamostat-interferon-alpha combination suppresses SARS-CoV-2 infection in vitro and in vivo

2021 ◽  
Author(s):  
Aleksandr Ianevski ◽  
Rouan Yo ◽  
Hilde Lysvand ◽  
Gunnveig Grodeland ◽  
Nicolas Legrand ◽  
...  
Keyword(s):  
Public Health ◽  
Patient Outcome ◽  
Cell Culture ◽  
Antiviral Activity ◽  
Critical Role ◽  
Low Doses ◽  
Important Mediator ◽  
The World

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here we address these challenges by combining Pegasys (IFNa) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNa and that both Serpin E1 and camostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.

scholarly journals ANTIVIRAL ACTIVITY OF AMINOCAPROIC ACID AGAINST INFECTIOUS BRONCHITIS CORONAVIRUS IN VITRO

2021 ◽  
Vol 29 (4) ◽  
pp. 35-39
Author(s):  
I. V. Dziublyk ◽  
O. P. Trokhimenko ◽  
S. O. Soloviov ◽  
G. L. Gumeniuk ◽  
O. Ya. Dziublyk ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Aminocaproic Acid ◽  
Antiviral Effect ◽  
Prototype Strain ◽  
In Vitro Cultivation ◽  
Infectious Bronchitis ◽  
Infectious Titer ◽  
Toxic Concentrations

I. V. Dziublyk, O. P. Trokhimenko, S. O. Soloviov, G. L. Gumeniuk, O. Ya. Dziublyk, N. I. Gumeniuk, O. K. Yakovenko Abstract The aim of the study is a preclinical evaluation of the antiviral activity of aminocaproic acid (ACA) against the prototype strain IBV (Infectious bronchitis virus) of Coronavirus family in vitro. Material and methods. During the research, modern methods were used to determine the cytotoxic effect of the evaluation on a monolayer of BHK-21 cell culture in vitro; cultivation, accumulation and determination of the infectious titer of IBV by cytopathic action on a monolayer of cell cultures; assessment of the antiviral effect of the drug — the establishment of the inhibitory concentration and the chemotherapeutic index (CTI) of ACA in various modes of drug administration: 2 hours before infection, simultaneously with infection and 2 hours after infection. Results. With the introduction of ACA 2 hours before infection, a decrease in the infectious titer of the IBV virus was not established. The antiviral activity of ACA was detected when the drug was added in 2 modes: simultaneously and 2 hours after infection. The introduction of ACА into the medium for cell cultivation at non-toxic concentrations of 7.91–15.82 mg / ml led to a decrease in the infectious titer of the virus by 1.4–2.0 lg TCD50 / 0.1 ml. The CTI of the ACA was 6 in the indicated concentrations and modes, which is an indicator of its promising potential for further studies of antiviral activity in vivo, including clinical studies. Conclusions. The direct antiviral effect of ACA against the prototype H-120 virus strain from the Coronaviridae family in vitro was revealed. The suppression of viral reproduction with an established low toxicity of the drug, a decrease in the infectious titer of IBV by 1.4–2.0 lg TCD50 / 0.1 ml and with a CTD equal to 6.0, indicate the prospects for further study of the antiviral properties of ACA in clinical trials. Key words: aminocaproic acid, coronavirus, antiviral activity.

scholarly journals MOXIDECTIN AND IVERMECTIN INHIBIT SARS-COV-2 REPLICATION IN VERO E6 CELLS BUT NOT IN HUMAN PRIMARY AIRWAY EPITHELIUM CELLS

2021 ◽  
Author(s):  
Nilima Dinesh Kumar ◽  
Bram M. ter Ellen ◽  
Ellen M. Bouma ◽  
Berit Troost ◽  
Denise P. I. van de Pol ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antiviral Effect ◽  
Vero Cells ◽  
In Vitro Models ◽  
World Health ◽  
Current Evidence ◽  
High Dose ◽  
Health Organization

Antiviral therapies are urgently needed to treat and limit the development of severe COVID-19 disease. Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 μM. These limited in vitro results triggered the investigation of ivermectin as a treatment option to alleviate COVID-19 disease. In April 2021, the World Health Organization stated, however, the following: “the current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive”. It is speculated that the in vivo concentration of ivermectin is too low to exert a strong antiviral effect. Here, we performed a head-to head comparison of the antiviral activity of ivermectin and the structurally related, but metabolically more stable, moxidectin in multiple in vitro models of SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Subsequent experiments revealed that the compounds predominantly act on a step after virus cell entry. Surprisingly, however, in human airway-derived cell models, moxidectin and ivermectin failed to inhibit SARS-CoV-2 infection, even at a concentration of 10 μM. These disappointing results call for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on Vero cells. Altogether, these findings suggest that, even by using a high-dose regimen of ivermectin or switching to another drug in the same class are unlikely to be useful for treatment against SARS-CoV-2 in humans.

scholarly journals Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

2014 ◽  
Vol 58 (7) ◽  
pp. 4042-4047 ◽  
Author(s):  
Amedeo De Nicolò ◽  
Marco Simiele ◽  
Andrea Calcagno ◽  
Adnan Mohamed Abdi ◽  
Stefano Bonora ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Antiviral Effect ◽  
Antiretroviral Drugs ◽  
Low Doses ◽  
Once Daily ◽  
Intracellular Concentrations

ABSTRACTProtease inhibitors are largely used for the treatment of HIV infection in combination with other antiretroviral drugs. Their improved pharmacokinetic profiles can be achieved through the concomitant administration of low doses of ritonavir (RTV), a protease inhibitor currently used as a booster, increasing the exposure of companion drugs. Since ritonavir-boosted regimens are associated with long-term adverse events, cobicistat, a CYP3A4 inhibitor without antiviral activity, has been developed. Recently, high intracellular concentrations of ritonavir in lymphocytes and monocytes were reported even when ritonavir was administered at low doses, so we aimed to compare its theoretical antiviral activity with those of the associated protease inhibitors. Intracellular concentrations of ritonavir and different protease inhibitors were determined through the same method. Inhibitory constants were obtained from the literature. The study enrolled 103 patients receiving different boosted protease inhibitors, darunavir-ritonavir 600 and 100 mg twice daily and 800 and 100 mg once daily (n= 22 and 4, respectively), atazanavir-ritonavir 300 and 100 mg once daily (n= 40), lopinavir-ritonavir 400 and 100 mg twice daily (n= 21), or tipranavir-ritonavir 500 and 200 mg twice daily (n= 16). According to the observed concentrations, we calculated the ratios between the intracellular concentrations of ritonavir and those of the companion protease inhibitor and between the theoretical viral protease reaction speeds with each drug, with and without ritonavir. The median ratios were 4.04 and 0.63 for darunavir-ritonavir twice daily, 2.49 and 0.74 for darunavir-ritonavir once daily, 0.42 and 0.74 for atazanavir-ritonavir, 0.57 and 0.95 for lopinavir-ritonavir, and 0.19 and 0.84 for tipranavir-ritonavir, respectively. Therefore, the antiviral effect of ritonavir was less than that of the concomitant protease inhibitors but, importantly, mostly with darunavir. Thus, furtherin vitroandin vivostudies of the RTV antiviral effect are warranted.

scholarly journals Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody

2020 ◽  
Vol 117 (31) ◽  
pp. 18754-18763 ◽  
Author(s):  
Mangaiarkarasi Asokan ◽  
Joana Dias ◽  
Cuiping Liu ◽  
Anna Maximova ◽  
Keenan Ernste ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Antiviral Effect ◽  
Effector Function ◽  
Decay Kinetics ◽  
Plasma Virus

Treatment of HIV infection with either antiretroviral (ARV) therapy or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ARVs and NAbs prevent new rounds of viral infection, but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor (FcγR)-mediated effector functions, which should affect the kinetics of plasma-virus decline. Here, we formally test the role of effector function in vivo by comparing the rate and timing of plasma-virus clearance in response to a single-dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic simian HIV (SHIV)-infected rhesus macaques, there was a 21% difference in slope of plasma-virus decline between NAb and NAb with reduced Fc function. NAb engineered to increase FcγRIII binding and improve antibody-dependent cellular cytotoxicity (ADCC) in vitro resulted in arming of effector cells in vivo, yet led to viral-decay kinetics similar to NAbs with reduced Fc function. These studies show that the predominant mechanism of antiviral activity of HIV NAbs is through inhibition of viral entry, but that Fc function can contribute to the overall antiviral activity, making them distinct from standard ARVs.

scholarly journals Moxidectin and ivermectin inhibit SARS-CoV-2 replication in Vero E6 cells but not in human primary airway epithelium cells

2021 ◽  
Author(s):  
Nilima Dinesh Kumar ◽  
Bram Ter Ellen ◽  
Ellen M Bouma ◽  
Berit Troost ◽  
Denise P. I van de Pol ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antiviral Effect ◽  
Vero Cells ◽  
In Vitro Models ◽  
World Health ◽  
Current Evidence ◽  
High Dose ◽  
Health Organization

Antiviral therapies are urgently needed to treat and limit the development of severe COVID-19 disease. Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 micromolar. These in vitro results triggered the investigation of ivermectin as a treatment option to alleviate COVID-19 disease. In April 2021, the World Health Organization stated, however, the following: "the current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive". It is speculated that the in vivo concentration of ivermectin is too low to exert a strong antiviral effect. Here, we performed a head-to head comparison of the antiviral activity of ivermectin and a structurally related, but metabolically more stable, moxidectin in multiple in vitro models of SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Subsequent experiments revealed that the compounds predominantly act on a step after virus cell entry. Surprisingly, however, in human airway-derived cell models, moxidectin and ivermectin failed to inhibit SARS-CoV-2 infection, even at a concentration of 10 micromolar. These disappointing results calls for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on Vero cells. Altogether, these findings suggest that, even by using a high-dose regimen of ivermectin or switching to another drug in the same class are unlikely to be useful for treatment against SARS-CoV-2 in humans.

scholarly journals Connecting Hydroxychloroquine In Vitro Antiviral Activity to In Vivo Concentration for Prediction of Antiviral Effect: A Critical Step in Treating Patients With Coronavirus Disease 2019

2020 ◽  
Author(s):  
Jianghong Fan ◽  
Xinyuan Zhang ◽  
Jiang Liu ◽  
Yuching Yang ◽  
Nan Zheng ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Tissue Concentration ◽  
Antiviral Effect ◽  
Effective Concentration ◽  
Critical Step ◽  
Dosing Regimens ◽  
Free Plasma

Abstract Translation of in vitro antiviral activity to the in vivo setting is crucial to identify potentially effective dosing regimens of hydroxychloroquine. In vitro 50%/90% maximal effective concentration values for hydroxychloroquine should be compared to the in vivo free extracellular tissue concentration, which is similar to the free plasma hydroxychloroquine concentration.

scholarly journals COVID 19: Resveratrol as a Potential Supplement to Mitigate the Cardiotoxicity Associated with Chloroquine and Hydroxychloroquine Treatment

2020 ◽  
Vol 11 (4) ◽  
pp. 11172-11186
Keyword(s):  
Antiviral Activity ◽  
Effective Treatment ◽  
Drug Repositioning ◽  
Cardiovascular Toxicity ◽  
Antiviral Efficacy ◽  
Antiviral Effects ◽  
The World ◽  
Recommended Therapy

The challenges of SARS-CoV-2 have frightened the world due to a lack of effective treatment. Many clinicians have adopted drug repositioning because of the urgent need to contain the viral pandemic. Several studies have demonstrated the in vitro and in vivo antiviral efficacy of chloroquine and hydroxychloroquine in the treatment of SARS-CoV-2. However, the cardiovascular toxicity of chloroquine and hydroxychloroquine stand as a limitation to their general use to treat SARS-CoV-2. Thus, it is necessitated the search for an adjuvant that could be used alongside these treatments to mitigate the undesired effect. The cardioprotective activity of resveratrol could serve to mitigate the cardiovascular toxicity of chloroquine and hydroxychloroquine. Its antioxidant and anti-inflammatory properties synergistically with chloroquine or hydroxychloroquine could also mitigate the antiviral activity of SARS-CoV-2. In this review, we explore chloroquine and hydroxychloroquine for SARS-CoV-2 treatment and suggest their synergetic use with resveratrol as a recommended therapy to mitigate cardiovascular toxicity and contribute to their antiviral effects.

scholarly journals Antiviral Effects of Geranylgeranylacetone: Enhancement of MxA Expression and Phosphorylation of PKR during Influenza Virus Infection

2003 ◽  
Vol 47 (9) ◽  
pp. 2914-2921 ◽  
Author(s):  
Masako Unoshima ◽  
Hideo Iwasaka ◽  
Junko Eto ◽  
Yoshiko Takita-Sonoda ◽  
Takayuki Noguchi ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Antiviral Activity ◽  
Influenza Virus Infection ◽  
Antiviral Effect ◽  
Initiation Factor ◽  
Potent Inducer ◽  
Α Subunit

ABSTRACT A cyclic polyisoprenoid compound, geranylgeranylacetone (GGA), has been used as antiulcer drug. GGA is also a potent inducer of heat shock proteins (HSPs). HSPs are considered to induce an antiviral effect; however, the detailed mechanism is unknown. To determine whether GGA might show antiviral activity and what the mechanism is, the effect of GGA against influenza virus (strain PR8) infection in vivo and in vitro was investigated. The results demonstrated that GGA treatment strongly suppressed the deleterious consequences of PR8 replication and was accompanied by an increase in HSP70 gene expression in mice. Results from in vitro analyses demonstrated that GGA significantly inhibited the synthesis of PR8-associated proteins and prominently enhanced expression of human myxovirus resistance 1 (MxA) followed by increased HSP70 transcription. Moreover, GGA augmented the expression of an interferon-inducible double-strand RNA-activated protein kinase (PKR) gene and promoted PKR autophosphorylation and concomitantly α subunit of eukaryotic initiation factor 2 phosphorylation during PR8 infection. It is proposed that GGA-induced HSP70 has potent antiviral activity by enhancement of antiviral factors and can clinically achieve protection from influenza virus infection.

Decellularized bone extracellular matrix in skeletal tissue engineering

2020 ◽  
Vol 48 (3) ◽  
pp. 755-764
Author(s):  
Benjamin B. Rothrauff ◽  
Rocky S. Tuan
Keyword(s):  
Tissue Engineering ◽  
Bone Regeneration ◽  
Tissue Regeneration ◽  
Animal Studies ◽  
Tumor Resection ◽  
Regenerative Capacity ◽  
Skeletal Tissue ◽  
Large Bone

Bone possesses an intrinsic regenerative capacity, which can be compromised by aging, disease, trauma, and iatrogenesis (e.g. tumor resection, pharmacological). At present, autografts and allografts are the principal biological treatments available to replace large bone segments, but both entail several limitations that reduce wider use and consistent success. The use of decellularized extracellular matrices (ECM), often derived from xenogeneic sources, has been shown to favorably influence the immune response to injury and promote site-appropriate tissue regeneration. Decellularized bone ECM (dbECM), utilized in several forms — whole organ, particles, hydrogels — has shown promise in both in vitro and in vivo animal studies to promote osteogenic differentiation of stem/progenitor cells and enhance bone regeneration. However, dbECM has yet to be investigated in clinical studies, which are needed to determine the relative efficacy of this emerging biomaterial as compared with established treatments. This mini-review highlights the recent exploration of dbECM as a biomaterial for skeletal tissue engineering and considers modifications on its future use to more consistently promote bone regeneration.

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