scholarly journals Novel Herbal Formulation Jing Si Exhibits Multiple Functions to Inhibit Replication Activity and Subsides Viral Load of COVID-19 Variants

2022 ◽  
Author(s):  
Yu-Jung Lin ◽  
Chien-Yi Chiang ◽  
Marthandam Asokan Shibu ◽  
San-Hua Su ◽  
Kingsley Theras Primus Dass ◽  
...  
Keyword(s):  
Viral Load ◽  
Viral Entry ◽  
Potential Candidate ◽  
Rdrp Activity ◽  
Colon Cells ◽  
Ability To Act ◽  
Frequent Mutations ◽  
3Cl Protease ◽  
Rdrp Assay ◽  
Replication Activity

Abstract Background: SARS-CoV-2 is susceptible to frequent mutations and gets transformed into variants therefore identifying novel multi targeting remedies is necessary in formulating strategies to overcome the pandemic. Methods: Traditional Chinese medicine based formula Jing Si herbal (JSH) was screened and analyzed by HPLC to evaluate its ability to act against infection by SARS-CoV-2 variants. The 3CL protease and RdRp assay kit were utilized to detect the enzyme activity. In order to determine the effect of JSH on the binding efficiency and viral penetration of SARS-CoV-2 variants, Calu-3 lung cells and Caco-2 colon cells were infected with fluorescent SARS-CoV-2 pseudo type lentiviruses. In addition, the effect of JSH (16.22 mg /mice/day and 48.66 mg/mice/day) on the viral load in SKH1J mice exposed to inhalation of luminescent SARS-CoV-2 variants for three days was determined. Results: The JSH was found to be effective in inhibiting the viral entry into Calu-3 and Caco-2 cells and in mice pre-treated with JSH for 3 days also inhibited the viral load exposed to different SARS-CoV-2 variants. Interestingly, JSH also decreased 3cL and RdRp activity thereby revealing the multi targeting nature of JSH and therefore will be a potential preventive SARS-CoV-2 infection.Conclusion: Taken together, our present results revealed that JSH could be a potential candidate for COVID-19 treatment.

In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA Dependent RNA polymerase (RdRp) and Essential Proteases

2020 ◽  
Vol 20 ◽  
Author(s):  
Trinath Chowdhury ◽  
Gourisankar Roymahapatra ◽  
Santi M. Mandal
Keyword(s):  
Rna Polymerase ◽  
Viral Entry ◽  
In Silico ◽  
Rna Dependent Rna Polymerase ◽  
Replication Complex ◽  
In Silico Study ◽  
Life Threatening ◽  
In Vivo Analysis ◽  
3Cl Protease

Background: COVID-19 is a life threatening novel corona viral infection to our civilization and spreading rapidly. Terrific efforts are generous by the researchers to search for a drug to control SARS-CoV-2. Methods: Here, a series of arsenical derivatives were optimized and analyzed with in silico study to search the inhibitor of RNA dependent RNA polymerase (RdRp), the major replication factor of SARS-CoV-2. All the optimized derivatives were blindly docked with RdRp of SARS-CoV-2 using iGEMDOCK v2.1. Results: Based on the lower idock score in the catalytic pocket of RdRp, darinaparsin (-82.52 kcal/mol) revealed most effective among them. Darinaparsin strongly binds with both Nsp9 replicase protein (-8.77 kcal/mol) and Nsp15 endoribonuclease (-8.3 kcal/mol) of SARS-CoV-2 as confirmed from the AutoDock analysis. During infection, the ssRNA of SARS-CoV2 is translated into large polyproteins forming viral replication complex by specific proteases like 3CL protease and papain protease. This is also another target to control the virus infection where darinaparsin also perform the inhibitory role to proteases of 3CL protease (-7.69 kcal/mol) and papain protease (-8.43 kcal/mol). Conclusion: In host cell, the furin protease serves as a gateway to the viral entry and darinaparsin docked with furin protease which revealed a strong binding affinity. Thus, screening of potential arsenic drugs would help in providing the fast invitro to in-vivo analysis towards development of therapeutics against SARS-CoV-2.

scholarly journals Dabigatran and Remdesivir Synergistically Inhibit Coronavirus Replication

2021 ◽  
Author(s):  
Alfred D. Nelson ◽  
Yan Bi ◽  
Baoan Ji
Keyword(s):  
Viral Load ◽  
Viral Entry ◽  
Serine Protease Inhibitor ◽  
Dependent Manner ◽  
Rt Pcr ◽  
Cytopathic Effects ◽  
Global Pandemic ◽  
Dose Dependent ◽  
Higher Doses

Abstract Background & Aims: Coronavirus-19 (COVID-19) due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) is an ongoing global pandemic causing more than three million deaths. Protease inhibitors had been shown to decrease viral entry. However, the role of dabigatran, an inhibitor of multiple proteases, on coronavirus remains unknown.Methods: MRC-5 cells, HCT-8, or Huh-7 cells were infected with Beta-coronavirus OC43 and SARS-CoV-2. Cytopathic effects (CPE) were monitored by imaging. Viral load was measured by quantitative RT-PCR. Viral protein was detected by Western blot.Results: Camostat, a serine protease inhibitor, had no effect on the replication of OC43 and SARS CoV-2 even at higher doses. Dabigatran inhibited replication, viral entry and CPE of OC43 in a dose-dependent manner. Dabigatran and Remdisivir synergistically inhibited OC43 virus replication. Conclusions: Dabigatran may be beneficial in treating SARS-CoV-2 both for anticoagulation and viral replication inhibition need to be evaluated further.

scholarly journals Effect of prophylactic use of intra-nasal oil formulations in the hamster model of Covid-19

2021 ◽  
Author(s):  
Zaigham Abbas Rizvi ◽  
Manas Ranjan Tripathy ◽  
Nishant Sharma ◽  
Sandeep Goswami ◽  
N Srikanth ◽  
...  
Keyword(s):  
Viral Load ◽  
Respiratory Tract ◽  
Viral Entry ◽  
Body Weight Loss ◽  
Lung Pathology ◽  
Upper Respiratory Tract ◽  
Hamster Model ◽  
Reduced Body ◽  
Upper Respiratory ◽  
Prophylactic Use

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection initiates with viral entry in upper respiratory tract leading to coronavirus disease 2019 (Covid-19). Severe Covid-19 is characterized by pulmonary pathologies associated with respiratory failure. Thus, therapeutics aimed at inhibiting entry of the virus or its internalization in the upper respiratory tract, are of interest. Herein, we report the prophylactic application of two intra-nasal formulations provided by the National Medicinal Plant Board (NMPB), Anu oil and Til tailya in SARS-CoV2 infection hamster model. Prophylactic nasal instillation of these oil formulations exhibited reduced viral load in lungs, and resulted in reduced body weight loss and pneumonitis. In line with reduced viral load, histopathlogical analysis revealed a reduction in lung pathology in Anu oil group as compared to the control infected group. However, Til tailya group did not show a significant reduction in lung pathology. Furthermore, molecular analysis using mRNA expression profiling indicated reduced expression of pro-inflammatory cytokines genes, including Th1 and Th17 cytokines for both the intra-nasal formulations as a result of decreased viral load. Together, the prophylactic intra-nasal application of Annu oil seems to be useful in limiting both the viral load and disease severity disease in SARS-CoV2 infection in hamster model.

scholarly journals Clinical study on black raspberry extract on the negative rate and effectiveness of patients with persistent human papilloma virus infection

2020 ◽  
Vol 12 ◽  
Author(s):  
Yifei Wang ◽  
Shengnan Li ◽  
Chunmin Hao
Keyword(s):  
Viral Load ◽  
Human Papilloma Virus ◽  
Persistent Infection ◽  
Control Group ◽  
Placebo Control ◽  
Potential Candidate ◽  
Black Raspberry ◽  
Papilloma Virus ◽  
Negative Rate ◽  
Hpv Viral Load

To investigate the negative rate and effectiveness of black raspberry extract in clearing persistent infection with human papilloma virus ( HPV), t hree hundred patients are included in the randomized, double blind, placebo controlled human trial for multicenter indication . The distribution ratio of the test ed group versus the control group is 2: 1 and the subject patients were given a preparation in the vagina before bed every other day, each dose was 3 g containing black raspberry extract (tested group) or placebo (control group). SPSS 20.0 was used for statistical analysis. Differences between groups were analyzed by the Rank Sum method or Chi square method. The results showed that 191 subjects in the tested group completed the trial , of which 139 subjects ( 72.8% were identified to have an effective clear ance of HPV ; 95 subjects in the control group completed the trial , of which only 15 subjects ( 15.8% were identified to have effective clearance of HPV. The difference between the two groups was statistically significant (  2 = P 0.001 ). The HPV viral load of the tested group was decreased from 224.7 RLU/CO to 88.6 RLU/CO whereas HPV viral load of the control group was ascend ed from 218.4 RLU/CO to 266.1 RLU/CO Thus , the present clinical observation suggested that b lack raspberry extract may be a potential candidate in targeting persistent infection with HPV.

scholarly journals Nafamostat Mesylate in lipid carrier for nasal SARS-CoV2 titer reduction in a hamster model

2020 ◽  
Author(s):  
Lisette Cornelissen ◽  
Esmee Hoefsmit ◽  
Disha Rao ◽  
Judith Lijnsvelt ◽  
Lucien van Keulen ◽  
...  
Keyword(s):  
Viral Load ◽  
Viral Entry ◽  
Infection Model ◽  
Protein Cleavage ◽  
Tissue Destruction ◽  
Hamster Model ◽  
Social Distancing ◽  
Nasal Application ◽  
User Friendly

AbstractSevere acute respiratory syndrome corona virus 2 (SARS-CoV-2) has been responsible for the largest pandemic in recent decades. After seemingly being in control due to consequent lock-downs and social distancing, the majority of countries faces currently a second wave of exponentially increasing infections, hospital referrals and deaths due to SARS-CoV-2-mediated disease (COVID-19). To date, no effective vaccination has been found, and wearing masks and social distancing are the only effective approaches to reduce further spreading.However, unwillingness in the societies to distance again and consequently wear masks might be reasons for the second SARS-CoV-2 infection wave. User-friendly chemicals interfering at the host site with viral entry might be an approach to contain the pandemic. In addition, such an approach would work synergistic with vaccinations that miss new virus mutants.Nafamostat (NM) has been shown in vitro to interfere with cellular virus entry by inhibition of the host transmembrane protease serine 2 (TMPRSS2), an enzyme required for SARS-CoV-2 spike protein cleavage, a prerequisite for cell entry.We hypothesized that nasal application of NM in a liposomal layer (as additional mechanical barrier) could lower the nasal viral load and subsequently reduce the severity of COVID-19. We found, indeed, that nasal viral load one day post single NM application, was lowered in a hamster SARS-CoV-2 infection model. However, severity of subsequent local tissue destruction and weight loss due to pneumonitis was not favorably altered.In conclusion, a single NM application reduced nasal viral load, but did not favorably improve the outcome of COVID-19, likely due to the short half-time of NM. Improvement of NM stability or repetitive application (which was not permitted in this animal model according to Dutch law) might circumvent these challenges.

scholarly journals Preclinical Evaluation of the HIV-1 Fusion Inhibitor L'644 as a Potential Candidate Microbicide

2012 ◽  
Vol 56 (5) ◽  
pp. 2347-2356 ◽  
Author(s):  
Sarah Harman ◽  
Carolina Herrera ◽  
Naomi Armanasco ◽  
Jeremy Nuttall ◽  
Robin J. Shattock
Keyword(s):  
Viral Entry ◽  
Hiv Transmission ◽  
Ex Vivo ◽  
Biological Fluids ◽  
Host Cells ◽  
Viral Escape ◽  
Escape Mutant ◽  
Potential Candidate ◽  
Preclinical Evaluation ◽  
Hiv 1

ABSTRACTTopical blockade of the gp41 fusogenic protein of HIV-1 is one possible strategy by which microbicides could prevent HIV transmission, working early against infection, by inhibiting viral entry into host cells. In this study, we examined the potential of gp41 fusion inhibitors (FIs) as candidate anti-HIV microbicides. Preclinical evaluation of four FIs, C34, T20, T1249, and L'644, was performed using cellular andex vivogenital and colorectal tissue explant models. Increased and sustained activity was detected for L'644, a cholesterol-derivatized version of C34, relative to the other FIs. The higher potency of L'644 was further increased with sustained exposure of cells or tissue to the compound. The activity of L'644 was not affected by biological fluids, and the compound was still active when tissue explants were treated after viral exposure. L'644 was also more active than other FIs against a viral escape mutant resistant to reverse transcriptase inhibitors (RTIs), demonstrating the potential of L'644 to be included as part of a multiactive antiretroviral (ARV) combination-based microbicide. These data support the further development of L'644 for microbicide application.

scholarly journals SARS-CoV-2 promotes RIPK1 activation to facilitate viral propagation

Cell Research ◽  
2021 ◽  
Author(s):  
Gang Xu ◽  
Ying Li ◽  
Shengyuan Zhang ◽  
Haoran Peng ◽  
Yunyun Wang ◽  
...  
Keyword(s):  
Viral Load ◽  
Transgenic Mice ◽  
Viral Entry ◽  
Human Lung ◽  
Therapeutic Option ◽  
Death Receptor ◽  
Central Component ◽  
Viral Propagation ◽  
Global Pandemic ◽  
Host Defense Response

AbstractCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the ongoing global pandemic that poses substantial challenges to public health worldwide. A subset of COVID-19 patients experience systemic inflammatory response, known as cytokine storm, which may lead to death. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important mediator of inflammation and cell death. Here, we examined the interaction of RIPK1-mediated innate immunity with SARS-CoV-2 infection. We found evidence of RIPK1 activation in human COVID-19 lung pathological samples, and cultured human lung organoids and ACE2 transgenic mice infected by SARS-CoV-2. Inhibition of RIPK1 using multiple small-molecule inhibitors reduced the viral load of SARS-CoV-2 in human lung organoids. Furthermore, therapeutic dosing of the RIPK1 inhibitor Nec-1s reduced mortality and lung viral load, and blocked the CNS manifestation of SARS-CoV-2 in ACE2 transgenic mice. Mechanistically, we found that the RNA-dependent RNA polymerase of SARS-CoV-2, NSP12, a highly conserved central component of coronaviral replication and transcription machinery, promoted the activation of RIPK1. Furthermore, NSP12 323L variant, encoded by the SARS-CoV-2 C14408T variant first detected in Lombardy, Italy, that carries a Pro323Leu amino acid substitution in NSP12, showed increased ability to activate RIPK1. Inhibition of RIPK1 downregulated the transcriptional induction of proinflammatory cytokines and host factors including ACE2 and EGFR that promote viral entry into cells. Our results suggest that SARS-CoV-2 may have an unexpected and unusual ability to hijack the RIPK1-mediated host defense response to promote its own propagation and that inhibition of RIPK1 may provide a therapeutic option for the treatment of COVID-19.

scholarly journals Direct detection of SARS-CoV-2 antisense and sense genomic RNA in human saliva by semi-autonomous fluorescence in situ hybridization: A proxy for contagiousness?

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256378
Author(s):  
Gijsbert J. Jansen ◽  
Marit Wiersma ◽  
Willem J. B. van Wamel ◽  
Inge D. Wijnberg
Keyword(s):  
Viral Load ◽  
Pilot Study ◽  
Viral Replication ◽  
Direct Detection ◽  
Human Saliva ◽  
Pathogen Transmission ◽  
Test Results ◽  
Genomic Rna ◽  
Replication Activity

Saliva is a matrix which may act as a vector for pathogen transmission and may serve as a possible proxy for SARS-CoV-2 contagiousness. Therefore, the possibility of detection of intracellular SARS-CoV-2 in saliva by means of fluorescence in situ hybridization is tested, utilizing probes targeting the antisense or sense genomic RNA of SARS-CoV-2. This method was applied in a pilot study with saliva samples collected from healthy persons and those presenting with mild or moderate COVID-19 symptoms. In all participants, saliva appeared a suitable matrix for the detection of SARS-CoV-2. Among the healthy, mild COVID-19-symptomatic and moderate COVID-19-symptomatic persons, 0%, 90% and 100% tested positive for SARS-CoV-2, respectively. Moreover, the procedure allows for simultaneous measurement of viral load (‘presence’, sense genomic SARS-CoV-2 RNA) and viral replication (‘activity’, antisense genomic SARS-CoV-2 RNA) and may yield qualitative results. In addition, the visualization of DNA in the cells in saliva provides an additional cytological context to the validity and interpretability of the test results. The method described in this pilot study may be a valuable diagnostic tool for detection of SARS-CoV-2, distinguishing between ‘presence’ (viral load) and ‘activity’ (viral replication) of the virus. Moreover, the method potentially gives more information about possible contagiousness.

scholarly journals Effect of Prophylactic Use of Intranasal Oil Formulations in the Hamster Model of COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Zaigham Abbas Rizvi ◽  
Manas Ranjan Tripathy ◽  
Nishant Sharma ◽  
Sandeep Goswami ◽  
N Srikanth ◽  
...  
Keyword(s):  
Viral Load ◽  
Respiratory Tract ◽  
Viral Entry ◽  
Body Weight Loss ◽  
Histopathological Analysis ◽  
Lung Pathology ◽  
Upper Respiratory Tract ◽  
Hamster Model ◽  
Reduced Body ◽  
Upper Respiratory

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection initiates with viral entry in the upper respiratory tract, leading to coronavirus disease 2019 (COVID-19). Severe COVID-19 is characterized by pulmonary pathologies associated with respiratory failure. Thus, therapeutics aimed at inhibiting the entry of the virus or its internalization in the upper respiratory tract are of interest. Herein, we report the prophylactic application of two intranasal formulations provided by the National Medicinal Plant Board (NMPB), Anu oil and til tailya, in the hamster model of SARS-CoV-2 infection. Prophylactic intra-nasal instillation of these oil formulations exhibited reduced viral load in lungs and resulted in reduced body weight loss and lung-pneumonitis. In line with reduced viral load, histopathological analysis revealed a reduction in lung pathology in the Anu oil group as compared to the control infected group. However, the til tailya group did not show a significant reduction in lung pathology. Furthermore, molecular analysis using mRNA expression profiling indicated reduced expression of pro-inflammatory cytokine genes, including Th1 and Th17 cytokines for both the intranasal formulations as a result of decreased viral load. Together, the prophylactic intranasal application of Anu oil seems to be useful in limiting both viral load and severity in SARS-CoV2 infection in the hamster model.

P1815The impact of PVB19 presence in myocardium in recent onset dilated cardiomyopathy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Krejci ◽  
P Hude ◽  
H Poloczkova ◽  
E Ozabalova ◽  
D Mlejnek ◽  
...  
Keyword(s):  
Viral Load ◽  
Dilated Cardiomyopathy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Recent Onset ◽  
Echocardiographic Parameters ◽  
One Year ◽  
Replication Activity

Abstract Introduction The most common virus in myocardium of patients with recent onset dilated cardiomyopathy (RODCM) is PVB19. Opinions on its pathogenicity are different. According to some, viral load has to be evaluated and if it is low, the PVB19 has no potential to induce inflammation. Others recommend assessment of viral replication, while “innocent” are those cases where replication activity is low. Purpose To compare the development of echocardiographic parameters in patients with RODCM with isolated presence of PVB19 in low viral load (below 500 copies per μg nucleic acid) against a group in which no virus was detected in the myocardium. Patient and methods 243 patients with RODCM, in 151 cases (62%), the virus was detected in the myocardium (PCR+ group), in 92 cases the finding was negative (PCR−; ie 38%). In the PCR+ group, PVB19 was captured in 135 cases (89% of all PCR+), in 121 cases of them was PVB19 the only one isolated virus (PCRPVB19+; 80% of all PCR+). The viral presence was assessed by real time PCR. Results In the PCR− group, the left ventricular ejection fraction (LVEF) was 23.5±7.2%, in the PCRPVB19+ group 24.6±7.1% (p=0.26). Left ventricle end-diastolic diameter (LVEDD) in PCR− was 66.4±8.9mm vs 65.5±7.9mm in PCRPVB19+ (p=0.42), right ventricle diameter (RV) 33.1±5.7mm vs. 33.4±5.2mm (p=0.69), TAPSE 19.5±4.1mm vs 18.9±4.0mm (p=0.28) and E/é 14.0±5.7 vs. 14.9±7.0 (p=0.32). In the 12-month control, LVEF in the PCR− was 35.5±12.3% (p<0.001 for comparison with baseline), in PCRPVB19+ 35.3±12.3% (p<0.001 for comparison with baseline; p=0.92 for difference between groups); LVEDD in PCR− was 62.0±9.3mm vs 62.1±9.3mm in PCRPVB19+ (both p<0.001 for comparison with baseline, p=0.91 for difference between groups), RV 31.6±5.5mm vs. 31.6±5.4mm (p=0.033, resp. p=0.003 for comparison with baseline; p=0.98 for difference between groups), TAPSE 20.7±4.3mm vs. 20.7±4.4mm (p=0.026, resp. p<0.001 for comparison with baseline; p=0.98 for difference between groups), and E/e' 10.3±4.1 vs. 10.4±4.1 (both p<0.001 for comparison with baseline; p=0.93 for difference between groups). Conclusion PVB19 presence in myocardium had no effect on the development of echocardiographic parameters in RODCM patients in one-year follow-up. Acknowledgement/Funding Supported by Ministry of Health of Czech Republic AZV Grant 16-30537A

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