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1.
Int J Mol Sci ; 23(4)2022 Feb 13.
Article in English | MEDLINE | ID: covidwho-1686819

ABSTRACT

The COVID-19 pandemic has evidenced the urgent need for the discovery of broad-spectrum antiviral therapies that could be deployed in the case of future emergence of novel viral threats, as well as to back up current therapeutic options in the case of drug resistance development. Most current antivirals are directed to inhibit specific viruses since these therapeutic molecules are designed to act on a specific viral target with the objective of interfering with a precise step in the replication cycle. Therefore, antimicrobial peptides (AMPs) have been identified as promising antiviral agents that could help to overcome this limitation and provide compounds able to act on more than a single viral family. We evaluated the antiviral activity of an amphibian peptide known for its strong antimicrobial activity against both Gram-positive and Gram-negative bacteria, namely Temporin L (TL). Previous studies have revealed that TL is endowed with widespread antimicrobial activity and possesses marked haemolytic activity. Therefore, we analyzed TL and a previously identified TL derivative (Pro3, DLeu9 TL, where glutamine at position 3 is replaced with proline, and the D-Leucine enantiomer is present at position 9) as well as its analogs, for their activity against a wide panel of viruses comprising enveloped, naked, DNA and RNA viruses. We report significant inhibition activity against herpesviruses, paramyxoviruses, influenza virus and coronaviruses, including SARS-CoV-2. Moreover, we further modified our best candidate by lipidation and demonstrated a highly reduced cytotoxicity with improved antiviral effect. Our results show a potent and selective antiviral activity of TL peptides, indicating that the novel lipidated temporin-based antiviral agents could prove to be useful additions to current drugs in combatting rising drug resistance and epidemic/pandemic emergencies.


Subject(s)
Amphibian Proteins/pharmacology , Amphibians/metabolism , Antimicrobial Cationic Peptides/pharmacology , Antiviral Agents/chemistry , DNA Viruses/drug effects , RNA Viruses/drug effects , Amino Acid Sequence , Amphibian Proteins/chemistry , Amphibian Proteins/metabolism , Animals , Antimicrobial Cationic Peptides/chemistry , Antimicrobial Cationic Peptides/metabolism , Antiviral Agents/pharmacology , Cell Survival/drug effects , Chlorocebus aethiops , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Lipids/chemistry , SARS-CoV-2/drug effects , Vero Cells
2.
Int J Mol Sci ; 23(2)2022 Jan 14.
Article in English | MEDLINE | ID: covidwho-1625084

ABSTRACT

Viral infections represent a serious threat to the world population and are becoming more frequent. The search and identification of broad-spectrum antiviral molecules is necessary to ensure new therapeutic options, since there is a limited availability of effective antiviral drugs able to eradicate viral infections, and consequently due to the increase of strains that are resistant to the most used drugs. Recently, several studies on antimicrobial peptides identified them as promising antiviral agents. In detail, amphibian skin secretions serve as a rich source of natural antimicrobial peptides. Their antibacterial and antifungal activities have been widely reported, but their exploitation as potential antiviral agents have yet to be fully investigated. In the present study, the antiviral activity of the peptide derived from the secretion of Rana tagoi, named AR-23, was evaluated against both DNA and RNA viruses, with or without envelope. Different assays were performed to identify in which step of the infectious cycle the peptide could act. AR-23 exhibited a greater inhibitory activity in the early stages of infection against both DNA (HSV-1) and RNA (MeV, HPIV-2, HCoV-229E, and SARS-CoV-2) enveloped viruses and, on the contrary, it was inactive against naked viruses (PV-1). Altogether, the results indicated AR-23 as a peptide with potential therapeutic effects against a wide variety of human viruses.


Subject(s)
Amphibian Proteins/pharmacology , Antiviral Agents/pharmacology , Ranidae/metabolism , Animals , Antimicrobial Cationic Peptides/pharmacology , Cell Survival/drug effects , Chlorocebus aethiops , DNA Viruses/drug effects , RNA Viruses/drug effects , SARS-CoV-2/drug effects , Vero Cells , Viral Envelope/drug effects , Viral Plaque Assay , Virus Diseases/drug therapy
3.
Viruses ; 13(5)2021 05 04.
Article in English | MEDLINE | ID: covidwho-1383920

ABSTRACT

Viral infections are responsible for several chronic and acute diseases in both humans and animals. Despite the incredible progress in human medicine, several viral diseases, such as acquired immunodeficiency syndrome, respiratory syndromes, and hepatitis, are still associated with high morbidity and mortality rates in humans. Natural products from plants or other organisms are a rich source of structurally novel chemical compounds including antivirals. Indeed, in traditional medicine, many pathological conditions have been treated using plant-derived medicines. Thus, the identification of novel alternative antiviral agents is of critical importance. In this review, we summarize novel phytochemicals with antiviral activity against human viruses and their potential application in treating or preventing viral disease.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , Drug Discovery , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Biological Products/chemistry , Biological Products/therapeutic use , DNA Viruses/drug effects , DNA Viruses/physiology , Drug Development , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , RNA Viruses/drug effects , RNA Viruses/physiology , Virus Diseases/diagnosis , Virus Diseases/drug therapy , Virus Diseases/etiology , Virus Diseases/metabolism , Virus Replication/drug effects
4.
Viruses ; 13(7)2021 06 27.
Article in English | MEDLINE | ID: covidwho-1289026

ABSTRACT

Many viruses, especially RNA viruses, utilize programmed ribosomal frameshifting and/or stop codon readthrough in their expression, and in the decoding of a few a UGA is dynamically redefined to specify selenocysteine. This recoding can effectively increase viral coding capacity and generate a set ratio of products with the same N-terminal domain(s) but different C-terminal domains. Recoding can also be regulatory or generate a product with the non-universal 21st directly encoded amino acid. Selection for translation speed in the expression of many viruses at the expense of fidelity creates host immune defensive opportunities. In contrast to host opportunism, certain viruses, including some persistent viruses, utilize recoding or adventitious frameshifting as part of their strategy to evade an immune response or specific drugs. Several instances of recoding in small intensively studied viruses escaped detection for many years and their identification resolved dilemmas. The fundamental importance of ribosome ratcheting is consistent with the initial strong view of invariant triplet decoding which however did not foresee the possibility of transitory anticodon:codon dissociation. Deep level dynamics and structural understanding of recoding is underway, and a high level structure relevant to the frameshifting required for expression of the SARS CoV-2 genome has just been determined.


Subject(s)
DNA Viruses/genetics , DNA Viruses/immunology , Histocompatibility Antigens Class I/immunology , Immune Evasion , RNA Viruses/genetics , Antiviral Agents/pharmacology , Codon, Terminator , DNA Viruses/drug effects , Frameshifting, Ribosomal , Histocompatibility Antigens Class I/genetics , Nucleic Acid Conformation , Peptides/immunology , Protein Biosynthesis , RNA Viruses/drug effects , RNA Viruses/immunology
5.
Sci China Life Sci ; 65(2): 341-361, 2022 02.
Article in English | MEDLINE | ID: covidwho-1245727

ABSTRACT

Viruses utilize cellular lipids and manipulate host lipid metabolism to ensure their replication and spread. Therefore, the identification of lipids and metabolic pathways that are suitable targets for antiviral development is crucial. Using a library of compounds targeting host lipid metabolic factors and testing them for their ability to block pseudorabies virus (PRV) and vesicular stomatitis virus (VSV) infection, we found that U18666A, a specific inhibitor of Niemann-Pick C1 (NPC1), is highly potent in suppressing the entry of diverse viruses including pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). NPC1 deficiency markedly attenuates viral growth by decreasing cholesterol abundance in the plasma membrane, thereby inhibiting the dynamics of clathrin-coated pits (CCPs), which are indispensable for clathrin-mediated endocytosis. Significantly, exogenous cholesterol can complement the dynamics of CCPs, leading to efficient viral entry and infectivity. Administration of U18666A improves the survival and pathology of PRV- and influenza A virus-infected mice. Thus, our studies demonstrate a unique mechanism by which NPC1 inhibition achieves broad antiviral activity, indicating a potential new therapeutic strategy against SARS-CoV-2, as well as other emerging viruses.


Subject(s)
Androstenes/pharmacology , Clathrin/physiology , Coated Pits, Cell-Membrane/physiology , DNA Viruses/drug effects , Niemann-Pick C1 Protein/physiology , RNA Viruses/drug effects , Virus Internalization/drug effects , DNA Viruses/physiology , Niemann-Pick C1 Protein/antagonists & inhibitors , RNA Viruses/physiology
6.
Int J Mol Sci ; 22(8)2021 Apr 17.
Article in English | MEDLINE | ID: covidwho-1206368

ABSTRACT

Viral infections cause a host of fatal diseases and seriously affect every form of life from bacteria to humans. Although most viral infections can receive appropriate treatment thereby limiting damage to life and livelihood with modern medicine and early diagnosis, new types of viral infections are continuously emerging that need to be properly and timely treated. As time is the most important factor in the progress of many deadly viral diseases, early detection becomes of paramount importance for effective treatment. Aptamers are small oligonucleotide molecules made by the systematic evolution of ligands by exponential enrichment (SELEX). Aptamers are characterized by being able to specifically bind to a target, much like antibodies. However, unlike antibodies, aptamers are easily synthesized, modified, and are able to target a wider range of substances, including proteins and carbohydrates. With these advantages in mind, many studies on aptamer-based viral diagnosis and treatments are currently in progress. The use of aptamers for viral diagnosis requires a system that recognizes the binding of viral molecules to aptamers in samples of blood, serum, plasma, or in virus-infected cells. From a therapeutic perspective, aptamers target viral particles or host cell receptors to prevent the interaction between the virus and host cells or target intracellular viral proteins to interrupt the life cycle of the virus within infected cells. In this paper, we review recent attempts to use aptamers for the diagnosis and treatment of various viral infections.


Subject(s)
Antiviral Agents/therapeutic use , Aptamers, Nucleotide/therapeutic use , Virus Diseases/diagnosis , Virus Diseases/drug therapy , Animals , DNA Viruses/drug effects , Humans , RNA Viruses/drug effects , Viral Proteins/drug effects , Virion/drug effects
7.
Eur J Med Chem ; 220: 113467, 2021 Aug 05.
Article in English | MEDLINE | ID: covidwho-1184952

ABSTRACT

Emerging and re-emerging viruses periodically cause outbreaks and epidemics all over the world, eventually leading to global events such as the current pandemic of the novel SARS-CoV-2 coronavirus infection COVID-19. Therefore, an urgent need for novel antivirals is crystal clear. Here we present the synthesis and evaluation of an antiviral activity of phenoxazine-based nucleoside analogs divided into three groups: (1) 8-alkoxy-substituted, (2) acyclic, and (3) carbocyclic. The antiviral activity was assessed against a structurally and phylogenetically diverse panel of RNA and DNA viruses from 25 species. Four compounds (11a-c, 12c) inhibited 4 DNA/RNA viruses with EC50 ≤ 20 µM. Toxicity of the compounds for the cell lines used for virus cultivation was negligible in most cases. In addition, previously reported and newly synthesized phenoxazine derivatives were evaluated against SARS-CoV-2, and some of them showed promising inhibition of reproduction with EC50 values in low micromolar range, although accompanied by commensurate cytotoxicity.


Subject(s)
Antiviral Agents/pharmacology , DNA Viruses/drug effects , Nucleosides/pharmacology , Oxazines/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/toxicity , Cell Line, Tumor , Chlorocebus aethiops , Dogs , Humans , Madin Darby Canine Kidney Cells , Microbial Sensitivity Tests , Molecular Structure , Nucleosides/chemical synthesis , Nucleosides/toxicity , Oxazines/chemical synthesis , Oxazines/toxicity , Structure-Activity Relationship , Vero Cells , Virus Replication/drug effects
8.
Mater Sci Eng C Mater Biol Appl ; 112: 110924, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-1017020

ABSTRACT

Research on highly effective antiviral drugs is essential for preventing the spread of infections and reducing losses. Recently, many functional nanoparticles have been shown to possess remarkable antiviral ability, such as quantum dots, gold and silver nanoparticles, nanoclusters, carbon dots, graphene oxide, silicon materials, polymers and dendrimers. Despite their difference in antiviral mechanism and inhibition efficacy, these functional nanoparticles-based structures have unique features as potential antiviral candidates. In this topical review, we highlight the antiviral efficacy and mechanism of these nanoparticles. Specifically, we introduce various methods for analyzing the viricidal activity of functional nanoparticles and the latest advances in antiviral functional nanoparticles. Furthermore, we systematically describe the advantages and disadvantages of these functional nanoparticles in viricidal applications. Finally, we discuss the challenges and prospects of antiviral nanostructures. This topic review covers 132 papers and will enrich our knowledge about the antiviral efficacy and mechanism of various functional nanoparticles.


Subject(s)
Antiviral Agents/chemistry , Nanoparticles/chemistry , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , DNA Viruses/drug effects , DNA Viruses/physiology , Graphite/chemistry , Metal Nanoparticles/chemistry , Metal Nanoparticles/toxicity , Nanoparticles/therapeutic use , Nanoparticles/toxicity , Polymers/chemistry , Quantum Dots/chemistry , Quantum Dots/therapeutic use , Quantum Dots/toxicity , Zika Virus/drug effects , Zika Virus Infection/drug therapy , Zika Virus Infection/veterinary
9.
Sci Rep ; 10(1): 4746, 2020 03 16.
Article in English | MEDLINE | ID: covidwho-740043

ABSTRACT

Ginkgolic acids (GA) are alkylphenol constituents of the leaves and fruits of Ginkgo biloba. GA has shown pleiotropic effects in vitro, including: antitumor effects through inhibition of lipogenesis; decreased expression of invasion associated proteins through AMPK activation; and potential rescue of amyloid-ß (Aß) induced synaptic impairment. GA was also reported to have activity against Escherichia coli and Staphylococcus aureus. Several mechanisms for this activity have been suggested including: SUMOylation inhibition; blocking formation of the E1-SUMO intermediate; inhibition of fatty acid synthase; non-specific SIRT inhibition; and activation of protein phosphatase type-2C. Here we report that GA inhibits Herpes simplex virus type 1 (HSV-1) by inhibition of both fusion and viral protein synthesis. Additionally, we report that GA inhibits human cytomegalovirus (HCMV) genome replication and Zika virus (ZIKV) infection of normal human astrocytes (NHA). We show a broad spectrum of fusion inhibition by GA of all three classes of fusion proteins including HIV, Ebola virus (EBOV), influenza A virus (IAV) and Epstein Barr virus (EBV). In addition, we show inhibition of a non-enveloped adenovirus. Our experiments suggest that GA inhibits virion entry by blocking the initial fusion event. Data showing inhibition of HSV-1 and CMV replication, when GA is administered post-infection, suggest a possible secondary mechanism targeting protein and DNA synthesis. Thus, in light of the strong effect of GA on viral infection, even after the infection begins, it may potentially be used to treat acute infections (e.g. Coronavirus, EBOV, ZIKV, IAV and measles), and also topically for the successful treatment of active lesions (e.g. HSV-1, HSV-2 and varicella-zoster virus (VZV)).


Subject(s)
Antiviral Agents/pharmacology , DNA Virus Infections/metabolism , DNA Viruses/drug effects , RNA Virus Infections/metabolism , RNA Viruses/drug effects , Salicylates/pharmacology , Viral Envelope Proteins/antagonists & inhibitors , Viral Fusion Proteins/antagonists & inhibitors , Animals , Astrocytes/metabolism , Chlorocebus aethiops , DNA Replication/drug effects , DNA Virus Infections/virology , DNA Viruses/genetics , DNA, Viral/genetics , HEK293 Cells , Humans , RNA Virus Infections/virology , RNA Viruses/genetics , Vero Cells , Viral Envelope Proteins/biosynthesis , Viral Fusion Proteins/biosynthesis , Virion/drug effects , Virus Internalization/drug effects , Virus Replication/drug effects
10.
Molecules ; 25(12)2020 Jun 16.
Article in English | MEDLINE | ID: covidwho-606990

ABSTRACT

BACKGROUND: In recent decades, several viruses have jumped from animals to humans, triggering sizable outbreaks. The current unprecedent outbreak SARS-COV-2 is prompting a search for new cost-effective therapies to combat this deadly pathogen. Suitably functionalized polysubstituted quinoxalines show very interesting biological properties (antiviral, anticancer, and antileishmanial), ensuring them a bright future in medicinal chemistry. OBJECTIVES: Focusing on the promising development of new quinoxaline derivatives as antiviral drugs, this review forms part of our program on the anti-infectious activity of quinoxaline derivatives. METHODS: Study compiles and discusses recently published studies concerning the therapeutic potential of the antiviral activity of quinoxaline derivatives, covering the literature between 2010 and 2020. RESULTS: A final total of 20 studies included in this review. CONCLUSIONS: This review points to a growing interest in the development of compounds bearing a quinoxaline moiety for antiviral treatment. This promising moiety with different molecular targets warrants further investigation, which may well yield even more encouraging results regarding this scaffold.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Quinoxalines/therapeutic use , COVID-19 , DNA Viruses/drug effects , Humans , Pandemics , Quinoxalines/chemistry , SARS-CoV-2 , Structure-Activity Relationship
11.
J Antibiot (Tokyo) ; 73(9): 593-602, 2020 09.
Article in English | MEDLINE | ID: covidwho-595987

ABSTRACT

Ivermectin proposes many potentials effects to treat a range of diseases, with its antimicrobial, antiviral, and anti-cancer properties as a wonder drug. It is highly effective against many microorganisms including some viruses. In this comprehensive systematic review, antiviral effects of ivermectin are summarized including in vitro and in vivo studies over the past 50 years. Several studies reported antiviral effects of ivermectin on RNA viruses such as Zika, dengue, yellow fever, West Nile, Hendra, Newcastle, Venezuelan equine encephalitis, chikungunya, Semliki Forest, Sindbis, Avian influenza A, Porcine Reproductive and Respiratory Syndrome, Human immunodeficiency virus type 1, and severe acute respiratory syndrome coronavirus 2. Furthermore, there are some studies showing antiviral effects of ivermectin against DNA viruses such as Equine herpes type 1, BK polyomavirus, pseudorabies, porcine circovirus 2, and bovine herpesvirus 1. Ivermectin plays a role in several biological mechanisms, therefore it could serve as a potential candidate in the treatment of a wide range of viruses including COVID-19 as well as other types of positive-sense single-stranded RNA viruses. In vivo studies of animal models revealed a broad range of antiviral effects of ivermectin, however, clinical trials are necessary to appraise the potential efficacy of ivermectin in clinical setting.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , DNA Viruses/drug effects , Ivermectin/therapeutic use , RNA Viruses/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/genetics , Cell Line/virology , Disease Models, Animal , Global Health , Humans , Ivermectin/chemistry , Ivermectin/pharmacology , Molecular Structure , SARS-CoV-2
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