Comparative efficacy of broad-spectrum antiviral agents as inhibitors of rotavirus replication in vitro

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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Mechanism-Based Covalent Neuraminidase Inhibitors with Broad-Spectrum Influenza Antiviral Activity

Science ◽

10.1126/science.1232552 ◽

2013 ◽

Vol 340 (6128) ◽

pp. 71-75 ◽

Cited By ~ 135

Author(s):

Jin-Hyo Kim ◽

Ricardo Resende ◽

Tom Wennekes ◽

Hong-Ming Chen ◽

Nicole Bance ◽

...

Keyword(s):

Broad Spectrum ◽

Antiviral Agents ◽

Neuraminidase Inhibitor ◽

New Class ◽

Development Of Resistance ◽

Spectrum Activity ◽

Future Utility ◽

Drug Resistant Strains ◽

Covalent Intermediate

Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor oseltamivir may limit their future utility. We report here on a new class of specific, mechanism-based anti-influenza drugs that function through the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and we confirm this mode of action with structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad-spectrum activity against drug-resistant strains in vitro. The similarity of their structure to that of the natural substrate and their mechanism-based design make these attractive antiviral candidates.

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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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Comparative efficacy of standard antihookworm drugs against various test nematodes

Journal of Helminthology ◽

10.1017/s0022149x00027875 ◽

1981 ◽

Vol 55 (4) ◽

pp. 273-278 ◽

Cited By ~ 17

Author(s):

Anuradha Misra ◽

P. K. S. Visen ◽

J. C. Katiyar

Keyword(s):

Broad Spectrum ◽

Lethal Effect ◽

Economic Importance ◽

Nippostrongylus Brasiliensis ◽

Comparative Efficacy ◽

Ancylostoma Ceylanicum ◽

Primary Screening ◽

Host Parasite ◽

Hookworm Infections

ABSTRACTThe chemotherapeutic responses of three test nematodes, Nippostrongylus brasilietxsis, Nematospiroidesdubius and Ancylostoma ceylanicum to standard antihookworm drugs were assessed in order to select asuitable host-parasite system for the primary screening of potential antihookworm compounds. N. dubiusbehaved inconsistently and, with some infections, required more drug to achieve 100% clearance. Nippostrongylus brasiliensis was found to be sensitive to thiabendazole, tetramisole and levamisole but the broad spectrum anthclmintic mebendazole was ineffective. A. ceylanicum was very sensitive to mebendazole, sensitive to tetramisole and levamisole and refractory to thiabendazole. In vitro, none of the compounds had any lethal effect against any of the nematodes, except mebendazole against A. ceylanicum.A. ceylanicum does occur in man and its chemotherapeutic reactions are similar to those of target hookworm infections of economic importance. As such, although not equally sensitive to standard anthelmintics, it is recommended for routine primary screening.

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Synthesis and In Vitro Study of Antiviral Activity of Glycyrrhizin Nicotinate Derivatives against HIV-1 Pseudoviruses and SARS-CoV-2 Viruses

Molecules ◽

10.3390/molecules27010295 ◽

2022 ◽

Vol 27 (1) ◽

pp. 295

Author(s):

Vladislav V. Fomenko ◽

Nadezhda B. Rudometova ◽

Olga I. Yarovaya ◽

Artem D. Rogachev ◽

Anastasia A. Fando ◽

...

Keyword(s):

Antiviral Activity ◽

Broad Spectrum ◽

Inhibitory Activity ◽

Antiviral Agents ◽

In Vitro Study ◽

Biologically Active ◽

Component Mixture ◽

Control Drug ◽

Hiv 1

When developing drugs against SARS-CoV-2, it is important to consider the characteristics of patients with different co-morbidities. People infected with HIV-1 are a particularly vulnerable group, as they may be at a higher risk than the general population of contracting COVID-19 with clinical complications. For such patients, drugs with a broad spectrum of antiviral activity are of paramount importance. Glycyrrhizinic acid (Glyc) and its derivatives are promising biologically active compounds for the development of such broad-spectrum antiviral agents. In this work, derivatives of Glyc obtained by acylation with nicotinic acid were investigated. The resulting preparation, Glycyvir, is a multi-component mixture containing mainly mono-, di-, tri- and tetranicotinates. The composition of Glycyvir was characterized by HPLC-MS/MS and its toxicity assessed in cell culture. Antiviral activity against three strains of SARS-CoV-2 was tested in vitro on Vero E6 cells by MTT assay. Glycyvir was shown to inhibit SARS-CoV-2 replication in vitro (IC502–8 μM) with an antiviral activity comparable to the control drug Remdesivir. In addition, Glycyvir exhibited marked inhibitory activity against HIV pseudoviruses of subtypes B, A6 and the recombinant form CRF63_02A (IC50 range 3.9–27.5 µM). The time-dependence of Glycyvir inhibitory activity on HIV pseudovirus infection of TZM-bl cells suggested that the compound interfered with virus entry into the target cell. Glycyvir is a promising candidate as an agent with low toxicity and a broad spectrum of antiviral action.

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Ionophore antibiotic X-206 is a potent and selective inhibitor of SARS-CoV-2 infection in vitro

10.1101/2020.06.14.149153 ◽

2020 ◽

Author(s):

Esben B. Svenningsen ◽

Jacob Thyrsted ◽

Julia Blay-Cadanet ◽

Han Liu ◽

Shaoquan Lin ◽

...

Keyword(s):

Broad Spectrum ◽

Antiviral Agents ◽

Host Cells ◽

World Population ◽

Antiviral Therapies ◽

The Family ◽

Pathogenic Viruses ◽

Antiviral Mechanism ◽

Treatment Of Infection

AbstractPandemic spread of emerging human pathogenic viruses such as the current SARS-CoV-2, poses both an immediate and future challenge to human health and society. Currently, effective treatment of infection with SARS-CoV-2 is limited and broad spectrum antiviral therapies to meet other emerging pandemics are absent leaving the World population largely unprotected. Here, we have identified distinct members of the family of polyether ionophore antibiotics with potent ability to inhibit SARS-CoV-2 replication and cytopathogenicity in cells. Several compounds from this class displayed more than 100-fold selectivity between viral-induced cytopathogenicity and inhibition of cell viability, however the compound X-206 displayed >500-fold selectivity and was furthermore able to inhibit viral replication even at sub-nM levels. The antiviral mechanism of the polyether ionophores is currently not understood in detail. We demonstrate, through unbiased bioactivity profiling, that their effects on the host cells differ from those of cationic amphiphiles such as hydroxychloroquine. Collectively, our data suggest that polyether ionophore antibiotics should be subject to further investigations as potential broad-spectrum antiviral agents.

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The New Generation hDHODH Inhibitor MEDS433 Hinders the In Vitro Replication of SARS-CoV-2 and OtherHuman Coronaviruses

Microorganisms ◽

10.3390/microorganisms9081731 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1731

Author(s):

Arianna Calistri ◽

Anna Luganini ◽

Barbara Mognetti ◽

Elizabeth Elder ◽

Giulia Sibille ◽

...

Keyword(s):

Antiviral Activity ◽

Broad Spectrum ◽

De Novo ◽

Antiviral Agents ◽

Embryonic Stem ◽

Potential Candidate ◽

In Vitro Replication ◽

Infected Cells ◽

New Generation

Although coronaviruses (CoVs) have long been predicted to cause zoonotic diseases and pandemics with high probability, the lack of effective anti-pan-CoVs drugs rapidly usable against the emerging SARS-CoV-2 actually prevented a promptly therapeutic intervention for COVID-19. Development of host-targeting antivirals could be an alternative strategy for the control of emerging CoVs infections, as they could be quickly repositioned from one pandemic event to another. To contribute to these pandemic preparedness efforts, here we report on the broad-spectrum CoVs antiviral activity of MEDS433, a new inhibitor of the human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidine biosynthesis pathway. MEDS433 inhibited the in vitro replication of hCoV-OC43 and hCoV-229E, as well as of SARS-CoV-2, at low nanomolar range. Notably, the anti-SARS-CoV-2 activity of MEDS433 against SARS-CoV-2 was also observed in kidney organoids generated from human embryonic stem cells. Then, the antiviral activity of MEDS433 was reversed by the addition of exogenous uridine or the product of hDHODH, the orotate, thus confirming hDHODH as the specific target of MEDS433 in hCoVs-infected cells. Taken together, these findings suggest MEDS433 as a potential candidate to develop novel drugs for COVID-19, as well as broad-spectrum antiviral agents exploitable for future CoVs threats.

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Phycobilins as potent food bioactive broad-spectrum inhibitor compounds against Mpro and PLpro of SARS-CoV-2 and other coronaviruses: A preliminary Study

10.1101/2020.11.21.392605 ◽

2020 ◽

Author(s):

Brahmaiah Pendyala ◽

Ankit Patras ◽

Chandravanu Dash

Keyword(s):

Binding Affinity ◽

Broad Spectrum ◽

In Silico ◽

Antiviral Agents ◽

First Century ◽

Inhibitor Activity ◽

Antiviral Compounds ◽

Preliminary Study ◽

Inhibitor Compounds

AbstractIn the twenty first century, we have witnessed three corona virus outbreaks; SARS in 2003, MERS in 2012 and ongoing pandemic COVID-19. To prevent outbreaks by novel mutant strains, we need broad-spectrum antiviral agents that are effective against wide array of coronaviruses. In this study, we scientifically investigated potent food bioactive broad-spectrum antiviral compounds by targeting Mpro and PLpro proteases of CoVs using in silico and in vitro approaches. The results revealed that phycocyanobilin (PCB) showed potential inhibitor activity against both proteases. PCB had best binding affinity to Mpro and PLpro with IC50 values of 71 μm and 62 μm, respectively. In addition, in silico studies of Mpro and PLpro enzymes of other human and animal CoVs indicated broad spectrum inhibitor activity of the PCB. Like PCB, other phycobilins such as phycourobilin (PUB), Phycoerythrobilin (PEB) and Phycoviolobilin (PVB) showed similar binding affinity to SARS-CoV-2 Mpro and PLpro

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