Broad-spectrum virucidal activity of bacterial secreted lipases against flaviviruses, SARS-CoV-2 and other enveloped viruses

AbstractViruses are the major aetiological agents of acute and chronic severe human diseases that place a tremendous burden on global public health and economy; however, for most viruses, effective prophylactics and therapeutics are lacking, in particular, broad-spectrum antiviral agents. Herein, we identified 2 secreted bacterial lipases from a Chromobacterium bacterium, named Chromobacterium antiviral effector-1 (CbAE-1) and CbAE-2, with a broad-spectrum virucidal activity against dengue virus (DENV), Zika virus (ZIKV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The CbAEs potently blocked viral infection in the extracellular milieu through their lipase activity. Mechanistic studies showed that this lipase activity directly disrupted the viral envelope structure, thus inactivating infectivity. A mutation of CbAE-1 in its lipase motif fully abrogated the virucidal ability. Furthermore, CbAE-2 presented low toxicity in vivo and in vitro, highlighting its potential as a broad-spectrum antiviral drug.

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Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

Medicinal Chemistry ◽

10.2174/1573406416666201120102905 ◽

2020 ◽

Vol 16 ◽

Author(s):

Xi He ◽

Wenjun Hu ◽

Fanhua Meng ◽

Xingzhou Li

Keyword(s):

Plasma Concentration ◽

Broad Spectrum ◽

Plasma Concentrations ◽

Antiviral Drug ◽

Systemic Exposure ◽

Pharmacokinetic Profile ◽

Hydroxyl Group ◽

First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

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Amphotericin B from antifungal to antiviral therapy: promising modern therapeutic branch

Research Results in Pharmacology ◽

10.3897/rrpharmacology.6.53649 ◽

2020 ◽

Vol 6 (2) ◽

pp. 57-65

Author(s):

Falah Hasan Obayes AL-Khikani

Keyword(s):

Amphotericin B ◽

Viral Infections ◽

Wide Spectrum ◽

Therapeutic Option ◽

Antiviral Drug ◽

Membrane Integrity ◽

Viral Envelope ◽

Antimicrobial Efficiency

Introduction: Amphotericin B (AmB) which belongs to the polyene group has a wide spectrum in vitro and in vivo antimicrobial activity against fungi and parasites, but resistance to AmB is rare despite extensive use. Material and methods: Atotal of 2530 articles were investigated in PubMed (n = 1525), Medline (n = 705), and Google Scholar (n = 300). From 2530 articles, only 61 studies were included in this review. All the short and full articles were searched that were scheduled to be published until April 2020. Results: After its discovery, AmB has been one of the most common first-line choices in treating systemic fungal infection for over seven decades from its discovery. Recently, some studies have focused on the potential antimicrobial action of AmB against some enveloped and non-enveloped viruses, such as human immunodeficiency virus, Japanese encephalitis virus, herpes simplex virus, and Rubella virus. Discussion: Among the invading pathogens, viruses constitute the most common ones,Due to the continuous spreading of viral infections with the rise in death numbers, new therapeutics development is urgent, as in general, some lethal viruses have no specific antiviral drugs or vaccines. So, this review may serve as an impetus for researchers working in the field of medical microbiology, vaccination, and antiviral drug design by discussing the most recent information about the antiviral action of AmB, as well as trying to provide a deeper understanding of major properties, mechanisms of action, immune system responses, and antimicrobial efficiency of AmB. Conclusion: Since AmB is expected to alter the structure of the viral envelope, membrane integrity of cells, and internal cellular organelles, besides its other unique properties, such as host immunomodulatory effects, this review suggested that AmB as an effective anti-fungi drug may hold the promise of formulating a novel therapeutic option to treat many dangerous viruses, including those for treating which there are no active drugs or vaccines.

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Nitazoxanide and JIB-04 have broad-spectrum antiviral activity and inhibit SARS-CoV-2 replication in cell culture and coronavirus pathogenesis in a pig model

10.1101/2020.09.24.312165 ◽

2020 ◽

Author(s):

Juhee Son ◽

Shimeng Huang ◽

Qiru Zeng ◽

Traci L. Bricker ◽

James Brett Case ◽

...

Keyword(s):

Antiviral Activity ◽

Body Weight Gain ◽

Antiviral Agents ◽

Cell Types ◽

Respiratory Syndrome Virus ◽

Transmissible Gastroenteritis Virus ◽

Global Public Health ◽

Dna And Rna

AbstractPathogenic coronaviruses represent a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified several small-molecule inhibitors that potently block the replication of the newly emerged severe acute respiratory syndrome virus 2 (SARS-CoV-2). Two compounds, nitazoxanide and JIB-04 inhibited SARS-CoV-2 replication in Vero E6 cells with an EC50 of 4.90 μM and 0.69 μM, respectively, with specificity indices of greater than 150. Both inhibitors had in vitro antiviral activity in multiple cell types against some DNA and RNA viruses, including porcine transmissible gastroenteritis virus. In an in vivo porcine model of coronavirus infection, administration of JIB-04 reduced virus infection and associated tissue pathology, which resulted in improved body weight gain and survival. These results highlight the potential utility of nitazoxanide and JIB-04 as antiviral agents against SARS-CoV-2 and other viral pathogens.

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Overcoming nonstructural protein 15-nidoviral uridylate-specific endoribonuclease (nsp15/NendoU) activity of SARS-CoV-2

Future Drug Discovery ◽

10.4155/fdd-2020-0012 ◽

2020 ◽

Vol 2 (3) ◽

pp. FDD42

Author(s):

Suranga L Senanayake

Keyword(s):

Broad Spectrum ◽

Nonstructural Protein ◽

Antiviral Agents ◽

Nucleoside Analogs ◽

Global Public Health ◽

Health Crisis ◽

Lethal Mutagenesis ◽

Double Hit ◽

Potential Inhibitors

COVID-19 has become the gravest global public health crisis since the Spanish Flu of 1918. Combination antiviral therapy with repurposed broad-spectrum antiviral agents holds a highly promising immediate treatment strategy, especially given uncertainties of vaccine efficacy and developmental timeline. Here, we describe a novel hypothetical approach: combining available broad-spectrum antiviral agents such as nucleoside analogs with potential inhibitors of NendoU, for example nsp15 RNA substrate mimetics. While only hypothesis-generating, this approach may constitute a ‘double-hit’ whereby two CoV-unique protein elements of the replicase–transcriptase complex are inhibited simultaneously; this may be an Achilles' heel and precipitate lethal mutagenesis in a coronavirus. It remains to be seen whether structurally optimized RNA substrate mimetics in combination with clinically approved and repurposed backbone antivirals can synergistically inhibit this endonuclease in vitro, thus fulfilling the ‘double-hit hypothesis’.

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An Historic Overview of Biological Response Modifiers as Antiviral Agents

Canadian Journal of Infectious Diseases ◽

10.1155/1992/979517 ◽

1992 ◽

Vol 3 (suppl b) ◽

pp. 34-40 ◽

Cited By ~ 1

Author(s):

Page S Morahan ◽

Aangelo J Pinto

Keyword(s):

Antiviral Activity ◽

Broad Spectrum ◽

Antiviral Agents ◽

Biological Response ◽

Natural Resistance ◽

Biological Response Modifiers ◽

Protective Effects ◽

Small Molecular Weight

A wide variety ofimmunomodulators/biological response modifiers (BRMs) has been demonstrated to provide broad spectrum antiviral activity against both RNA and DNA viruses in several animal species. Dramatic decreases in mortality, reduced virus titres in tissues and reduced histopathology can be produced. The antivirally effective agents include microbially derived materials, polyanions, cytokines and chemically diverse small molecular weight chemicals. The greatest protective effects are observed with prophylactic treatment. although early therapeutic treatment can also be effective. Little direct antiviral activity can be observed in vitro. The findings suggest induction by BRMs of antiviral mediators in vivo early in the course of viral pathogenesis, before the virus has become sequestered in a privileged site or too much infectious virus has been produced for natural resistance to have an impact, immunomodulators are pleiotropic in their immunomodulatory effects, and it has been difficult to establish whether one cell type or mediator is critical for the observed broad spectrum antiviral activity. Therefore, the mechanisms of antiviral action of immunomodulators remain unclear for most systems, but probably involve enhancement of natural immune responses. While no unified antiviral mechanism among different immunomodulators has yet emerged, interferon induction remains a major hypothesis.

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Nanomaterials Designed for Antiviral Drug Delivery Transport across Biological Barriers

Pharmaceutics ◽

10.3390/pharmaceutics12020171 ◽

2020 ◽

Vol 12 (2) ◽

pp. 171 ◽

Cited By ~ 23

Author(s):

Florina-Daniela Cojocaru ◽

Doru Botezat ◽

Ioannis Gardikiotis ◽

Cristina-Mariana Uritu ◽

Gianina Dodi ◽

...

Keyword(s):

Drug Delivery ◽

Viral Infections ◽

Antiviral Agents ◽

Antiviral Drug ◽

Chemical Properties ◽

Antiviral Therapies ◽

Physico Chemical ◽

Socio Economic Impact

Viral infections are a major global health problem, representing a significant cause of mortality with an unfavorable continuously amplified socio-economic impact. The increased drug resistance and constant viral replication have been the trigger for important studies regarding the use of nanotechnology in antiviral therapies. Nanomaterials offer unique physico-chemical properties that have linked benefits for drug delivery as ideal tools for viral treatment. Currently, different types of nanomaterials namely nanoparticles, liposomes, nanospheres, nanogels, nanosuspensions and nanoemulsions were studied either in vitro or in vivo for drug delivery of antiviral agents with prospects to be translated in clinical practice. This review highlights the drug delivery nanosystems incorporating the major antiviral classes and their transport across specific barriers at cellular and intracellular level. Important reflections on nanomedicines currently approved or undergoing investigations for the treatment of viral infections are also discussed. Finally, the authors present an overview on the requirements for the design of antiviral nanotherapeutics.

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Antiviral Compounds from Myxobacteria

Microorganisms ◽

10.3390/microorganisms6030073 ◽

2018 ◽

Vol 6 (3) ◽

pp. 73 ◽

Cited By ~ 5

Author(s):

Lucky Mulwa ◽

Marc Stadler

Keyword(s):

Broad Spectrum ◽

Viral Infections ◽

Antiviral Agents ◽

Antiviral Drug ◽

Public Health Issue ◽

Target Cells ◽

Global Public Health ◽

Drug Candidates ◽

Antiviral Compounds ◽

Spectrum Activity

Viral infections including human immunodeficiency virus (HIV), cytomegalovirus (CMV), hepatitis B virus (HBV), and hepatitis C virus (HCV) pose an ongoing threat to human health due to the lack of effective therapeutic agents. The re-emergence of old viral diseases such as the recent Ebola outbreaks in West Africa represents a global public health issue. Drug resistance and toxicity to target cells are the major challenges for the current antiviral agents. Therefore, there is a need for identifying agents with novel modes of action and improved efficacy. Viral-based illnesses are further aggravated by co-infections, such as an HIV patient co-infected with HBV or HCV. The drugs used to treat or manage HIV tend to increase the pathogenesis of HBV and HCV. Hence, novel antiviral drug candidates should ideally have broad-spectrum activity and no negative drug-drug interactions. Myxobacteria are in the focus of this review since they produce numerous structurally and functionally unique bioactive compounds, which have only recently been screened for antiviral effects. This research has already led to some interesting findings, including the discovery of several candidate compounds with broad-spectrum antiviral activity. The present review looks at myxobacteria-derived antiviral secondary metabolites.

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Antiviral activity of silymarin and baicalein against dengue virus

Scientific Reports ◽

10.1038/s41598-021-98949-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Zhao Xuan Low ◽

Brian Ming OuYong ◽

Pouya Hassandarvish ◽

Chit Laa Poh ◽

Babu Ramanathan

Keyword(s):

Antiviral Activity ◽

Dengue Virus ◽

Viral Entry ◽

Dengue Infection ◽

Antiviral Agents ◽

Antiviral Drug ◽

Vero Cells ◽

Viral Envelope ◽

E Protein

AbstractDengue is an arthropod-borne viral disease that has become endemic and a global threat in many countries with no effective antiviral drug available currently. This study showed that flavonoids: silymarin and baicalein could inhibit the dengue virus in vitro and were well tolerated in Vero cells with a half-maximum cytotoxic concentration (CC50) of 749.70 µg/mL and 271.03 µg/mL, respectively. Silymarin and baicalein exerted virucidal effects against DENV-3, with a selective index (SI) of 10.87 and 21.34, respectively. Baicalein showed a better inhibition of intracellular DENV-3 progeny with a SI of 7.82 compared to silymarin. Baicalein effectively blocked DENV-3 attachment (95.59%) to the Vero cells, while silymarin prevented the viral entry (72.46%) into the cells, thus reducing viral infectivity. Both flavonoids showed promising antiviral activity against all four dengue serotypes. The in silico molecular docking showed that silymarin could bind to the viral envelope (E) protein with a binding affinity of − 8.5 kcal/mol and form hydrogen bonds with the amino acids GLN120, TRP229, ASN89, and THR223 of the E protein. Overall, this study showed that silymarin and baicalein exhibited potential anti-DENV activity and could serve as promising antiviral agents for further development against dengue infection.

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In Vitro and in Vivo Antiviral Activity of Mizoribine Against Foot-And-Mouth Disease Virus

Molecules ◽

10.3390/molecules24091723 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1723 ◽

Cited By ~ 2

Author(s):

Shi-Fang Li ◽

Mei-Jiao Gong ◽

Yue-Feng Sun ◽

Jun-Jun Shao ◽

Yong-Guang Zhang ◽

...

Keyword(s):

Antiviral Activity ◽

Early Stage ◽

Antiviral Agents ◽

Antiviral Drug ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Mouth Disease Virus ◽

Foot And Mouth

Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals, which has significant economic consequences in affected countries. As the currently available vaccines against FMD provide no protection until 4–7 days post-vaccination, the only alternative method to control the spread of FMD virus (FMDV) during outbreaks is the application of antiviral agents. Hence, it is important to identify effective antiviral agents against FMDV infection. In this study, we found that mizoribine has potent antiviral activity against FMDV replication in IBRS-2 cells. A time-of-drug-addition assay demonstrated that mizoribine functions at the early stage of replication. Moreover, mizoribine also showed antiviral effect on FMDV in vivo. In summary, these results revealed that mizoribine could be a potential antiviral drug against FMDV.

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Antiviral efficacy in vivo of the anti-human immunodeficiency virus bicyclam SDZ SID 791 (JM 3100), an inhibitor of infectious cell entry.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.3.750 ◽

1996 ◽

Vol 40 (3) ◽

pp. 750-754 ◽

Cited By ~ 70

Author(s):

R Datema ◽

L Rabin ◽

M Hincenbergs ◽

M B Moreno ◽

S Warren ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Antiviral Agents ◽

Antiviral Drug ◽

Virus Production ◽

Significant Inhibition ◽

Cell Entry ◽

Immunodeficiency Virus ◽

Antiviral Chemotherapy

SID 791, a bicyclam inhibiting human immunodeficiency virus (HIV) replication in vitro by blocking virus entry into cells, is an effective inhibitor of virus production and of depletion of human CD4+ T cells in HIV type 1-infected SCID-hu Thy/Liv mice. Steady levels of 100 ng of SID 791 or higher per ml in plasma resulted in statistically significant inhibition of p24 antigen formation. Daily injections of SID 791 caused a dose-dependent decrease in viremia, and this inhibition could be potentiated by coadministration of zidovudine or didanose. The present study suggests that SID 791 alone or in combination with licensed antiviral agents may decrease the virus load in HIV-infected patients and, by extension, that the infectious cell entry step is a valid target for antiviral chemotherapy of HIV disease. The SCID-hu Thy/Liv model in effect provides a rapid means of assessing the potential of compounds with novel modes of antiviral action, as well as the potential of antiviral drug combinations.

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