Potent Antiviral Activity Against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids

Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of antiviral drugs involves the identification of a unique viral target, followed by the design of an agent that addresses that target. Antimicrobial peptides (AMPs) represent a novel source of potential antiviral drugs. AMPs have been shown to inactivate numerous different enveloped viruses through the disruption of their viral envelopes. However, the clinical development of AMPs as antimicrobial therapeutics has been hampered by a number of factors, especially their structure as peptides. We have examined the antiviral potential of peptoid mimics of AMPs (sequence-specific N-substituted glycine oligomers). These peptoids have the distinct advantage of being insensitive to proteases, and also exhibit increased bioavailability and stability. Our results demonstrate that several peptoids exhibit potent in vitro antiviral activity against both HSV-1 and SARS-CoV-2 when incubated prior to infection. Visualization by cryo-EM shows viral envelope disruption similar to what has been observed with AMP activity against other viruses. This suggests a common or biomimetic mechanism, possibly due to the differences between the phospholipid head group makeup of viral envelopes and host cell membranes. Furthermore, we observed no cytotoxicity against primary cultures of oral epithelial cells, thus underscoring the potential of this class of molecules as safe and effective broad-spectrum antiviral agents.

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Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids

Pharmaceuticals ◽

10.3390/ph14040304 ◽

2021 ◽

Vol 14 (4) ◽

pp. 304

Author(s):

Gill Diamond ◽

Natalia Molchanova ◽

Claudine Herlan ◽

John A. Fortkort ◽

Jennifer S. Lin ◽

...

Keyword(s):

Antiviral Activity ◽

Primary Cultures ◽

Antiviral Drugs ◽

Viral Envelope ◽

Distinct Advantage ◽

Head Group ◽

Molecular Features ◽

Viral Envelopes ◽

Hsv 1

Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of antiviral drugs involves the identification of a unique viral target, followed by the design of an agent that addresses that target. Antimicrobial peptides (AMPs) represent a novel source of potential antiviral drugs. AMPs have been shown to inactivate numerous different enveloped viruses through the disruption of their viral envelopes. However, the clinical development of AMPs as antimicrobial therapeutics has been hampered by a number of factors, especially their enzymatically labile structure as peptides. We have examined the antiviral potential of peptoid mimics of AMPs (sequence-specific N-substituted glycine oligomers). These peptoids have the distinct advantage of being insensitive to proteases, and also exhibit increased bioavailability and stability. Our results demonstrate that several peptoids exhibit potent in vitro antiviral activity against both HSV-1 and SARS-CoV-2 when incubated prior to infection. In other words, they have a direct effect on the viral structure, which appears to render the viral particles non-infective. Visualization by cryo-EM shows viral envelope disruption similar to what has been observed with AMP activity against other viruses. Furthermore, we observed no cytotoxicity against primary cultures of oral epithelial cells. These results suggest a common or biomimetic mechanism, possibly due to the differences between the phospholipid head group makeup of viral envelopes and host cell membranes, thus underscoring the potential of this class of molecules as safe and effective broad-spectrum antiviral agents. We discuss how and why differing molecular features between 10 peptoid candidates may affect both antiviral activity and selectivity.

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Antimalarial drugs—are they beneficial in rheumatic and viral diseases?—considerations in COVID-19 pandemic

Clinical Rheumatology ◽

10.1007/s10067-021-05805-5 ◽

2021 ◽

Author(s):

Bogna Grygiel-Górniak

Keyword(s):

Connective Tissue ◽

Viral Infections ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Antiviral Drugs ◽

In Vivo Studies ◽

Viral Diseases ◽

Cardiac Complications

AbstractThe majority of the medical fraternity is continuously involved in finding new therapeutic schemes, including antimalarial medications (AMDs), which can be useful in combating the 2019-nCoV: coronavirus disease (COVID-19). For many decades, AMDs have been widely used in the treatment of malaria and various other anti-inflammatory diseases, particularly to treat autoimmune disorders of the connective tissue. The review comprises in vitro and in vivo studies, original studies, clinical trials, and consensus reports for the analysis, which were available in medical databases (e.g., PubMed). This manuscript summarizes the current knowledge about chloroquine (CQ)/hydroxychloroquine (HCQ) and shows the difference between their use, activity, recommendation, doses, and adverse effects on two groups of patients: those with rheumatic and viral diseases (including COVID-19). In the case of connective tissue disorders, AMDs are prescribed for a prolonged duration in small doses, and their effect is observed after few weeks, whereas in the case of viral infections, they are prescribed in larger doses for a short duration to achieve a quick saturation effect. In rheumatic diseases, AMDs are well tolerated, and their side effects are rare. However, in some viral diseases, the effect of AMDs is questionable or not so noticeable as suggested during the initial prognosis. They are mainly used as an additive therapy to antiviral drugs, but recent studies have shown that AMDs can diminish the efficacy of some antiviral drugs and may cause respiratory, kidney, liver, and cardiac complications.

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Antiviral Activity of the G-Quadruplex Ligand TMPyP4 against Herpes Simplex Virus-1

Viruses ◽

10.3390/v13020196 ◽

2021 ◽

Vol 13 (2) ◽

pp. 196

Author(s):

Sara Artusi ◽

Emanuela Ruggiero ◽

Matteo Nadai ◽

Beatrice Tosoni ◽

Rosalba Perrone ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Dna Replication ◽

Herpes Simplex ◽

Antiviral Activity ◽

Herpes Simplex Virus 1 ◽

Tem Analysis ◽

Infected Cells ◽

Simplex Virus ◽

Hsv 1

The herpes simplex virus 1 (HSV-1) genome is extremely rich in guanine tracts that fold into G-quadruplexes (G4s), nucleic acid secondary structures implicated in key biological functions. Viral G4s were visualized in HSV-1 infected cells, with massive virus cycle-dependent G4-formation peaking during viral DNA replication. Small molecules that specifically interact with G4s have been shown to inhibit HSV-1 DNA replication. We here investigated the antiviral activity of TMPyP4, a porphyrin known to interact with G4s. The analogue TMPyP2, with lower G4 affinity, was used as control. We showed by biophysical analysis that TMPyP4 interacts with HSV-1 G4s, and inhibits polymerase progression in vitro; in infected cells, it displayed good antiviral activity which, however, was independent of inhibition of virus DNA replication or entry. At low TMPyP4 concentration, the virus released by the cells was almost null, while inside the cell virus amounts were at control levels. TEM analysis showed that virus particles were trapped inside cytoplasmatic vesicles, which could not be ascribed to autophagy, as proven by RT-qPCR, western blot, and immunofluorescence analysis. Our data indicate a unique mechanism of action of TMPyP4 against HSV-1, and suggest the unprecedented involvement of currently unknown G4s in viral or antiviral cellular defense pathways.

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Entry of Herpes Simplex Virus Type 1 into Primary Sensory Neurons In Vitro Is Mediated by Nectin-1/HveC

Journal of Virology ◽

10.1128/jvi.77.5.3307-3311.2003 ◽

2003 ◽

Vol 77 (5) ◽

pp. 3307-3311 ◽

Cited By ~ 53

Author(s):

Sarah M. Richart ◽

Scott A. Simpson ◽

Claude Krummenacher ◽

J. Charles Whitbeck ◽

Lewis I. Pizer ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Sensory Neurons ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Primary Cultures ◽

Simplex Virus ◽

Hsv 1

ABSTRACT Primary cultures of rat and mouse sensory neurons were used to study the entry of herpes simplex virus type 1 (HSV-1). Soluble, truncated nectin-1 but not HveA prevented viral entry. Antibodies against nectin-1 also blocked infection of rat neurons. These results indicate that nectin-1 is the primary receptor for HSV-1 infection of sensory neurons.

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In vitro activity of human recombinant alpha-2b interferon against SARS-CoV-2 virus

Voprosy Virusologii ◽

10.36233/0507-4088-13 ◽

2021 ◽

Vol 66 (2) ◽

pp. 123-128

Author(s):

S. Ya. Loginova ◽

V. N. Shсhukina ◽

S. V. Savenko ◽

S. V. Borisevich

Keyword(s):

Cell Culture ◽

Antiviral Activity ◽

Viral Infections ◽

Complete Suppression ◽

Antiviral Efficacy ◽

Prevention And Treatment ◽

Proven Efficacy ◽

High Antiviral Activity

Introduction. The pandemic spread of a new coronavirus infection, COVID-19, has caused a global emergency and attracted the attention of public health professionals and the population of all countries. A significant increase in the number of new cases of SARS-CoV-2 infection demonstrates the urgency of finding drugs effective against this pathogen.The aim of this work was to evaluate the in vitro antiviral efficacy of human recombinant alpha-2b interferon (IFN-α2b) against SARS-CoV-2 virus.Material and methods. The experiments had been carried out on Vero Cl008, the continuous line of African green monkey (Chlorocebus sabaeus) kidney cells. The effectiveness of the drugs was assessed by the suppression of viral reproduction in vitro. The biological activity was determined using titration of a virus-containing suspension in a Vero Cl008 cell culture by the formation of negative colonies.Results. The antiviral efficacy of the IFN-α2b-based medications, which have a high safety profile and proven efficacy in the prevention and treatment of influenza and acute respiratory viral infections (ARVI), has been studied against the new pandemic SARS-CoV-2 virus in vitro experiments in Vero C1008 cell culture. IFN-α2b effectively inhibits the reproduction of the virus when applied both 24 hrs before and 2 hrs after infection. In the IFN-α2b concentration range 102–106 IU/ml a complete suppression of the reproduction of the SARS-CoV-2 virus had been demonstrated.Discussion. IFN-α2b demonstrated in vitro high antiviral activity against SARS-CoV-2. In addition, the substance has a high chemotherapeutic index (>1000).Conclusion. Medications for intranasal use based on IFN-α2b have high antiviral activity and are promising drugs for in vivo study in terms of prevention and treatment of COVID-19.

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Antiviral activity of 1,4-disubstituted-1,2,3-triazoles against HSV-1 in vitro

Antiviral Therapy ◽

10.3851/imp3387 ◽

2021 ◽

Author(s):

Daiane J Viegas ◽

Verônica D da Silva ◽

Camilla D Buarque ◽

David C Bloom ◽

Paula A Abreu

Keyword(s):

Antiviral Activity ◽

Hsv 1

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Antiherpesvirus Activity of the Combination of 5-iodo-2′-deoxycytidine with methotrexate: An in vitro and in vivo Study

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029400500501 ◽

1994 ◽

Vol 5 (5) ◽

pp. 283-289

Author(s):

C. Cremonesi ◽

C. Scarpini ◽

R. Bianchi ◽

A. Radaelli ◽

M. Gimelli ◽

...

Keyword(s):

Antiviral Activity ◽

Dihydrofolate Reductase ◽

Reductase Inhibitor ◽

Cellular Viability ◽

Cutaneous Lesions ◽

Guinea Pig Model ◽

Simplex Virus ◽

Hsv 1

We evaluated the in vitro and in vivo antiviral activity of the deoxyribonucleoside analogue 5-iodo-2′-deoxycytidine (IDC) combined with the dihydrofolate reductase inhibitor methotrexate (MTX) on herpes simplex virus types 1 and 2 (HSV-1, HSV-2). The IDC-MTX combination synergistically inhibited HSV-1 and HSV-2 replication in vitro at concentrations that did not reduce cellular viability and was very effective in reducing the severity of cutaneous lesions in the experimental guinea pig model in vivo. The antiviral activity of the IDC-MTX combination in guinea pigs was also compared with that of acyclovir and was demonstrated to be higher.

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Tryptophan Trimers and Tetramers Inhibit Dengue and Zika Virus Replication by Interfering with Viral Attachment Processes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02130-19 ◽

2020 ◽

Vol 64 (3) ◽

Author(s):

Antonios Fikatas ◽

Peter Vervaeke ◽

Belén Martínez-Gualda ◽

Olaia Martí-Marí ◽

Sam Noppen ◽

...

Keyword(s):

Antiviral Activity ◽

Zika Virus ◽

Antiviral Agent ◽

Viral Envelope ◽

Pharmacokinetic Studies ◽

Host Cell Membrane ◽

Viral Attachment ◽

Virus Attachment ◽

Domain Iii

ABSTRACT Here, we report a class of tryptophan trimers and tetramers that inhibit (at low micromolar range) dengue and Zika virus infection in vitro. These compounds (AL family) have three or four peripheral tryptophan moieties directly linked to a central scaffold through their amino groups; thus, their carboxylic acid groups are free and exposed to the periphery. Structure-activity relationship (SAR) studies demonstrated that the presence of extra phenyl rings with substituents other than COOH at the N1 or C2 position of the indole side chain is a requisite for the antiviral activity against both viruses. The molecules showed potent antiviral activity, with low cytotoxicity, when evaluated on different cell lines. Moreover, they were active against laboratory and clinical strains of all four serotypes of dengue virus as well as a selected group of Zika virus strains. Additional mechanistic studies performed with the two most potent compounds (AL439 and AL440) demonstrated an interaction with the viral envelope glycoprotein (domain III) of dengue 2 virus, preventing virus attachment to the host cell membrane. Since no antiviral agent is approved at the moment against these two flaviviruses, further pharmacokinetic studies with these molecules are needed for their development as future therapeutic/prophylactic drugs.

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Ultrastructure of the Effects of Pyrrolidine-fused Chlorins on the Replication of HSV-1

Microscopy and Microanalysis ◽

10.1017/s1431927608089666 ◽

2008 ◽

Vol 14 (S3) ◽

pp. 137-138

Author(s):

António P.A. Matos ◽

Ana R.N. Santos ◽

Maria F. Caeiro ◽

Maria A.F. Faustino ◽

M.G.P.M.S. Neves ◽

...

Keyword(s):

Antiviral Activity ◽

Antiviral Drugs ◽

Cell Complex ◽

New Drugs ◽

Viral Resistance ◽

Porphyrin Derivatives ◽

Cellular Target ◽

Immunocompromised Hosts ◽

Hsv 1

Currently, only few antiviral drugs of proven effectiveness exist against virus of the Herpesviridae family and viral resistance to these drugs, especially in the immunocompromised hosts, has encouraged research for new drugs. Some porphyrin derivatives revealed a significant antiviral activity against HSV-1 virus. However the cellular target of the porphyrin derivatives in the virus-cell complex remains unknown.

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