scholarly journals HTCC as a Polymeric Inhibitor of SARS-CoV-2 and MERS-CoV

2020 ◽  
Author(s):  
Aleksandra Milewska ◽  
Ying Chi ◽  
Artur Szczepanski ◽  
Emilia Barreto-Duran ◽  
Agnieszka Dabrowska ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Ex Vivo ◽  
Multiorgan Failure ◽  
Highly Pathogenic ◽  
Modified Chitosan ◽  
Human Airway Epithelium ◽  
Human Coronaviruses ◽  
Novel Coronavirus ◽  
Global And Local

Among seven coronaviruses that infect humans, three (SARS-CoV, MERS-CoV, and the newly identified SARS-CoV-2) are associated with a severe, life-threatening respiratory infection and multiorgan failure. We previously proposed that the cationically modified chitosan, N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC) is a potent inhibitor of HCoV-NL63. Next, we demonstrated the broad-spectrum antiviral activity of the compound, as it inhibited all low pathogenic human coronaviruses (HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1). Here, using in vitro and ex vivo model of human airway epithelium, we show that HTCC effectively blocks MERS-CoV and SARS-CoV-2 infection. We also confirmed the mechanism of action for these two viruses, showing that the polymer blocks the virus entry to the host cell by interaction with the S protein. IMPORTANCE The beginning of 2020 brought us information about the novel coronavirus emerging in China. Rapid research resulted in the characterization of the pathogen, which appeared to be a member of the SARS-like cluster, commonly seen in bats. Despite the global and local efforts, the virus escaped the health care measures and rapidly spread in China and later globally, officially causing a pandemic and global crisis in March 2020. At present, different scenarios are being written to contain the virus, but the development of novel anticoronavirals for all highly pathogenic coronaviruses remains the major challenge. Here, we describe the antiviral activity of previously developed by us HTCC compound, which may be used as a potential inhibitor of currently circulating highly pathogenic coronaviruses – SARS-CoV-2 and MERS-CoV.

scholarly journals HTCC as a highly effective polymeric inhibitor of SARS-CoV-2 and MERS-CoV

2020 ◽  
Author(s):  
Aleksandra Milewska ◽  
Ying Chi ◽  
Artur Szczepanski ◽  
Emilia Barreto-Duran ◽  
Kevin Liu ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
The Novel ◽  
Highly Pathogenic ◽  
Global Crisis ◽  
Potential Inhibitor ◽  
Highly Effective ◽  
Novel Coronavirus ◽  
Global And Local

ABSTRACTThe beginning of 2020 brought us information about the novel coronavirus emerging in China. Rapid research resulted in the characterization of the pathogen, which appeared to be a member of the SARS-like cluster, commonly seen in bats. Despite the global and local efforts, the virus escaped the healthcare measures and rapidly spread in China and later globally, officially causing a pandemic and global crisis in March 2020. At present, different scenarios are being written to contain the virus, but the development of novel anticoronavirals for all highly pathogenic coronaviruses remains the major challenge. Here, we describe the antiviral activity of previously developed by us HTCC compound (N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride), which may be used as potential inhibitor of currently circulating highly pathogenic coronaviruses – SARS-CoV-2 and MERS-CoV.

scholarly journals Nanodroplet-Benzalkonium Chloride Formulation Demonstrates In Vitro and Ex- Vivo Broad-Spectrum Antiviral Activity Against SARS-CoV-2 and other Enveloped Viruses

2021 ◽  
Author(s):  
Jessie Pannu ◽  
Susan Ciotti ◽  
Shyamala Ganesan ◽  
George Arida ◽  
Chad Costley ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Benzalkonium Chloride ◽  
Ex Vivo ◽  
Viral Disease ◽  
Influenza B ◽  
Human Coronavirus ◽  
Enveloped Viruses ◽  
Nasal Irritation

Abstract Objective: The Covid-19 pandemic has highlighted the importance of aerosolized droplets inhaled into the nose in the transmission of respiratory viral disease. Inactivating pathogenic viruses at the nasal port of entry may reduce viral loads, thereby reducing infection, transmission and spread. In this communication, we demonstrate safe and broad anti-viral activity of oil-in-water nanoemulsion (nanodroplet) formulation containing the potent antiseptic 0.13% Benzalkonium Chloride (NE-BZK). Results: We have demonstrated that NE-BZK exhibits broad-spectrum, long-lasting antiviral activity with >99.9% in vitro killing of enveloped viruses including SARS-CoV-2, human coronavirus, RSV, and influenza B. In vitro and ex-vivo studies demonstrated continued killing of >99.99% of human coronavirus with diluted NE-BZK and persistent for 8 hours post application, respectively. The repeated application of NE-BZK, twice daily for 2 weeks into rabbit nostrils demonstrated its safety with no nasal irritation. These findings demonstrate that formulating BZK into the proprietary nanodroplets offers a safe and effective antiviral and a significant addition to strategies to combat the spread of respiratory viral infectious diseases.

In vitro Antiviral Activity of Kabasura Kudineer - Siddha Polyherbal Formulation Against Novel Coronavirus (SARS-CoV-2)

2021 ◽  
Author(s):  
Shree Devi MS ◽  
Sathiyarajeswaran P ◽  
Karthik L ◽  
Kanakavalli K. ◽  
Chandru S. ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Polyherbal Formulation ◽  
Novel Coronavirus

scholarly journals In Vitro Combinations of Baloxavir Acid and Other Inhibitors against Seasonal Influenza A Viruses

Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1139
Author(s):  
Liva Checkmahomed ◽  
Blandine Padey ◽  
Andrés Pizzorno ◽  
Olivier Terrier ◽  
Manuel Rosa-Calatrava ◽  
...  
Keyword(s):  
Cell Viability ◽  
Influenza A ◽  
Ex Vivo ◽  
Synergistic Effects ◽  
Prolonged Treatment ◽  
Influenza A Viruses ◽  
Human Airway Epithelium ◽  
Influenza A H1n1 ◽  
Approved Drugs

Two antiviral classes, the neuraminidase inhibitors (NAIs) and polymerase inhibitors (baloxavir marboxil and favipiravir) can be used to prevent and treat influenza infections during seasonal epidemics and pandemics. However, prolonged treatment may lead to the emergence of drug resistance. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we evaluated in vitro combinations of baloxavir acid (BXA) and other approved drugs against influenza A(H1N1)pdm09 and A(H3N2) subtypes. The determination of an effective concentration inhibiting virus cytopathic effects by 50% (EC50) for each drug and combination indexes (CIs) were based on cell viability. CompuSyn software was used to determine synergism, additivity or antagonism between drugs. Combinations of BXA and NAIs or favipiravir had synergistic effects on cell viability against the two influenza A subtypes. Those effects were confirmed using a physiological and predictive ex vivo reconstructed human airway epithelium model. On the other hand, the combination of BXA and ribavirin showed mixed results. Overall, BXA stands as a good candidate for combination with several existing drugs, notably oseltamivir and favipiravir, to improve in vitro antiviral activity. These results should be considered for further animal and clinical evaluations.

scholarly journals Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

2011 ◽  
Vol 55 (4) ◽  
pp. 1650-1660 ◽  
Author(s):  
Alamelu Mahalingam ◽  
Adam P. Simmons ◽  
Shweta R. Ugaonkar ◽  
Karen M. Watson ◽  
Charlene S. Dezzutti ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Mechanical Stability ◽  
Culture Media ◽  
Ex Vivo ◽  
Hydroxyethyl Cellulose ◽  
Therapeutic Window ◽  
Formulation Development ◽  
Drug Release Profile ◽  
Hiv 1

ABSTRACTPyrimidinediones, a novel class of compounds, have previously been shown to possess antiviral activity at nanomolar concentrations. One member of this class of compounds, IQP-0528, was selected as the lead molecule for formulation development owing to its stability at physiologically relevant conditions, wide therapeutic window, and antiviral activity in the nanomolar range. Here, we report the development of two vaginal gels—3.0% hydroxyethyl cellulose (HEC) formulation and a 0.65% Carbopol formulation—for the sustained delivery of IQP-0528. Stability studies under accelerated conditions confirmed the chemical stability of IQP-0528 and mechanical stability of the gel formulation for 3 months.In vitrorelease studies revealed that diffusion-controlled release of IQP-0528 occurred over 6 h, with an initial lag time of approximately 1 h. Based on the drug release profile, the 3.0% HEC gel was selected as the lead formulation for safety and activity evaluations. Thein vitroandex vivosafety evaluations showed no significant loss in cell viability or significant inflammatory response after treatment with a 3.0% HEC gel containing 0.25% IQP-0528. In anin vitroHIV-1 entry inhibition assay, the lead formulation showed an 50% effective concentration of 0.14 μg/ml for gel in culture media, which corresponds to ∼0.001 μM IQP-0528. The antiviral activity was further confirmed by using polarized cervical explants, in which the formulation showed complete protection against HIV infection. In summary, these results are encouraging and warrant further evaluation of IQP-0528 gel formulations inin vivomodels, as well as the development of alternative formulations for the delivery of IQP-0528 as a microbicide.

scholarly journals Identification of a conserved neutralizing epitope present on spike proteins from all highly pathogenic coronaviruses

2021 ◽  
Author(s):  
Yimin Huang ◽  
Annalee W. Nguyen ◽  
Ching-Lin Hsieh ◽  
Rui Silva ◽  
Oladimeji S. Olaluwoye ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Conformational Epitope ◽  
Neutralizing Epitope ◽  
Highly Pathogenic ◽  
Exchange Mass Spectrometry ◽  
Global Pandemic ◽  
Hydrogen Deuterium ◽  
Deuterium Exchange Mass Spectrometry ◽  
Human Coronaviruses

ABSTRACTThree pathogenic human coronaviruses have emerged, with SARS-CoV-2 causing a global pandemic. While therapeutic antibodies targeting the SARS-2 spike currently focus on the poorly conserved receptor-binding domain, targeting essential neutralizing epitopes on the more conserved S2 domain may provide broader protection. We report three antibodies, binding epitopes conserved on the pre-fusion MERS, SARS-1 and SARS-2 spike S2 domains. Antibody 3A3 binds a conformational epitope with ~2.5 nM affinity and neutralizes in in vitro SARS-2 cell fusion and pseudovirus assays. Hydrogen-deuterium exchange mass spectrometry identified residues 980-1006 in the flexible hinge region at the S2 apex as the 3A3 epitope, consistent with binding to natural and engineered spike variants. This location at the spike trimer interface suggests 3A3 prevents the S2 conformational rearrangements required for virus-host cell fusion. This work defines a highly conserved vulnerable site on the SARS-2 S2 domain and may help guide the design of pan-protective spike immunogens.TEASERA conserved, neutralizing epitope in the S2 domain of coronavirus spike was identified as a target for pan-coronavirus therapy and vaccination.

scholarly journals The rocaglate CR-31-B (-) inhibits SARS-CoV-2 replication at non-cytotoxic, low nanomolar concentrations in vitro and ex vivo

2020 ◽  
Author(s):  
Christin Müller ◽  
Wiebke Obermann ◽  
Nadja Karl ◽  
Hans-Guido Wendel ◽  
Gaspar Taroncher-Oldenburg ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Ex Vivo ◽  
Rna Virus ◽  
Mrna Translation ◽  
Hemorrhagic Fever ◽  
Airway Epithelial Cells ◽  
Initiation Factor ◽  
Protein Accumulation ◽  
Hemorrhagic Fever Virus

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a betacoronavirus in the subgenus Sarbecovirus causes a respiratory disease with varying symptoms referred to as coronavirus disease 2019 (COVID-19) and is responsible for a pandemic that started in early 2020. With no vaccines or effective antiviral treatments available, and infection and fatality numbers continuing to increase globally, the quest for novel therapeutic solutions remains an urgent priority. Rocaglates, a class of plant-derived cyclopenta[b]benzofurans, exhibit broad-spectrum antiviral activity against positive- and negative-sense RNA viruses. This compound class inhibits eukaryotic initiation factor 4A (eIF4A)-dependent mRNA translation initiation, resulting in strongly reduced viral RNA translation. The synthetic rocaglate CR-31-B (-) has previously been shown to inhibit the replication of human coronaviruses, such as HCoV-229E and MERS-CoV, as well as Zika-, Lassa-, Crimean Congo hemorrhagic fever virus in primary cells. Here, we assessed the antiviral activity of CR-31-B (-) against SARS-CoV-2 using both in vitro and ex vivo cell culture models. In African green monkey Vero E6 cells, CR-31-B (-) inhibited SARS-CoV-2 replication with an EC50 of ~1.8 nM. In line with this, viral protein accumulation and replication/transcription complex formation were found to be strongly reduced by this compound. In an ex vivo infection system using human airway epithelial cells, CR-31-B (-) was found to cause a massive reduction of SARS-CoV-2 titers by about 4 logs to nearly non-detectable levels. The data reveal a potent anti-SARS-CoV-2 activity by CR-31-B (-), corroborating previous results obtained for other coronaviruses and supporting the idea that rocaglates may be used in first-line antiviral intervention strategies against novel and emerging RNA virus outbreaks.

scholarly journals The Secretome Profiling of a Pediatric Airway Epithelium Infected with hRSV Identified Aberrant Apical/Basolateral Trafficking and Novel Immune Modulating (CXCL6, CXCL16, CSF3) and Antiviral (CEACAM1) Proteins

2020 ◽  
Vol 19 (5) ◽  
pp. 793-807 ◽  
Author(s):  
Olivier Touzelet ◽  
Lindsay Broadbent ◽  
Stuart D. Armstrong ◽  
Waleed Aljabr ◽  
Elaine Cloutman-Green ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Airway Epithelium ◽  
Ex Vivo ◽  
Lymphocyte Activation ◽  
Respiratory Epithelium ◽  
Airway Epithelial ◽  
Pediatric Airway ◽  
Antiviral Responses ◽  
Syncytial Virus

The respiratory epithelium comprises polarized cells at the interface between the environment and airway tissues. Polarized apical and basolateral protein secretions are a feature of airway epithelium homeostasis. Human respiratory syncytial virus (hRSV) is a major human pathogen that primarily targets the respiratory epithelium. However, the consequences of hRSV infection on epithelium secretome polarity and content remain poorly understood. To investigate the hRSV-associated apical and basolateral secretomes, a proteomics approach was combined with an ex vivo pediatric human airway epithelial (HAE) model of hRSV infection (data are available via ProteomeXchange and can be accessed at https://www.ebi.ac.uk/pride/ with identifier PXD013661). Following infection, a skewing of apical/basolateral abundance ratios was identified for several individual proteins. Novel modulators of neutrophil and lymphocyte activation (CXCL6, CSF3, SECTM1 or CXCL16), and antiviral proteins (BST2 or CEACAM1) were detected in infected, but not in uninfected cultures. Importantly, CXCL6, CXCL16, CSF3 were also detected in nasopharyngeal aspirates (NPA) from hRSV-infected infants but not healthy controls. Furthermore, the antiviral activity of CEACAM1 against RSV was confirmed in vitro using BEAS-2B cells. hRSV infection disrupted the polarity of the pediatric respiratory epithelial secretome and was associated with immune modulating proteins (CXCL6, CXCL16, CSF3) never linked with this virus before. In addition, the antiviral activity of CEACAM1 against hRSV had also never been previously characterized. This study, therefore, provides novel insights into RSV pathogenesis and endogenous antiviral responses in pediatric airway epithelium.

scholarly journals A Lipopeptide HIV-1/2 Fusion Inhibitor with Highly Potent In Vitro, Ex Vivo, and In Vivo Antiviral Activity

2017 ◽  
Vol 91 (11) ◽  
Author(s):  
Huihui Chong ◽  
Jing Xue ◽  
Shengwen Xiong ◽  
Zhe Cong ◽  
Xiaohui Ding ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
Ex Vivo ◽  
Rhesus Macaques ◽  
Fusion Inhibitor ◽  
Clinical Use ◽  
Viral Fusion ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Peptides derived from the C-terminal heptad repeat (CHR) region of the human immunodeficiency virus type 1 (HIV-1) fusogenic protein gp41 are potent viral entry inhibitors, and currently, enfuvirtide (T-20) is the only one approved for clinical use; however, emerging drug resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, an HIV-2 sequence, intrahelical salt bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad, and long-lasting antiviral activity. In in vitro studies, LP-19 efficiently inhibited HIV-1-, HIV-2-, and simian immunodeficiency virus (SIV)-mediated cell fusion, viral entry, and infection, and it was highly active against diverse subtypes of primary HIV-1 isolates and inhibitor-resistant mutants. Ex vivo studies demonstrated that LP-19 exhibited dramatically increased anti-HIV activity and an extended half-life in rhesus macaques. In short-term monotherapy, LP-19 reduced viral loads to undetectable levels in acutely and chronically simian-human immunodeficiency virus (SHIV)-infected monkeys. Therefore, this study offers an ideal HIV-1/2 fusion inhibitor for clinical development and emphasizes the importance of the viral fusion step as a drug target. IMPORTANCE The peptide drug T-20 is the only viral fusion inhibitor in the clinic, which is used for combination therapy of HIV-1 infection; however, it requires a high dosage and easily induces drug resistance, calling for a new drug with significantly improved pharmaceutical profiles. Here, we have developed a short-lipopeptide-based fusion inhibitor, termed LP-19, which mainly targets the conserved gp41 pocket site and shows highly potent inhibitory activity against HIV-1, HIV-2, and even SIV isolates. LP-19 exhibits dramatically increased antiviral activity and an extended half-life in rhesus macaques, and it has potent therapeutic efficacy in SHIV-infected monkeys, highlighting its high potential as a new viral fusion inhibitor for clinical use.

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