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938 KiB

Open AccessArticle

In Vitro Anti-HMPV Activity of Meroditerpenoids from Marine Alga Stypopodium zonale (Dictyotales)

by Gabriella Mendes, Angélica Ribeiro Soares, Lorena Sigiliano, Fernanda Machado, Carlos Kaiser, Nelilma Romeiro, Lísia Gestinari, Norma Santos and Maria Teresa Villela Romanos

Molecules 2011, 16(10), 8437-8450; https://doi.org/10.3390/molecules16108437 - 10 Oct 2011

Cited by 27 | Viewed by 5650

Abstract

In this paper, we evaluated the antiviral activity against HMPV replication of crude extract of the marine algae Stypopodium zonale and of two meroditerpenoids obtained from it, atomaric acid and epitaondiol, and a methyl ester derivative of atomaric acid. Their selectivity indexes were [...] Read more.

In this paper, we evaluated the antiviral activity against HMPV replication of crude extract of the marine algae Stypopodium zonale and of two meroditerpenoids obtained from it, atomaric acid and epitaondiol, and a methyl ester derivative of atomaric acid. Their selectivity indexes were 20.78, >56.81, 49.26 and 12.82, respectively. Compared to ribavirin, the substances showed a relatively low cytotoxicity on LLC-MK2 cells, with a significant antiviral activity, inhibiting at least 90% of viral replication in vitro, which demonstrates the potential of these marine natural products to combat infections caused by HMPV in vitro. Full article

(This article belongs to the Special Issue Antivirals)

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592 KiB

Open AccessArticle

Synthesis of Quinolin-2-one Alkaloid Derivatives and Their Inhibitory Activities against HIV-1 Reverse Transcriptase

by Pi Cheng, Qiong Gu, Wei Liu, Jian-Feng Zou, Yang-Yong Ou, Zhong-Yong Luo and Jian-Guo Zeng

Molecules 2011, 16(9), 7649-7661; https://doi.org/10.3390/molecules16097649 - 07 Sep 2011

Cited by 24 | Viewed by 8897

Abstract

Based on an established common pharmacophore of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNTTIs), a series of quinolin-2-one derivatives were synthesized and assayed for their in vitro activities against HIV-1 reverse transcriptase (RT) for the first time. Some of the tested compounds were active [...] Read more.

Based on an established common pharmacophore of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNTTIs), a series of quinolin-2-one derivatives were synthesized and assayed for their in vitro activities against HIV-1 reverse transcriptase (RT) for the first time. Some of the tested compounds were active against HIV-1 RT. Compounds 4a2 and 4d2 showed inhibitory activities with IC₅₀ values of 0.21 and 0.15 mM, respectively, with a mode of interaction with RT residues of the allosteric pocket similar to that of efavirenz. Full article

(This article belongs to the Special Issue Antivirals)

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551 KiB

Open AccessArticle

Effect of ASP2151, a Herpesvirus Helicase-Primase Inhibitor, in a Guinea Pig Model of Genital Herpes

by Kiyomitsu Katsumata, Koji Chono, Kenji Sudo, Yasuaki Shimizu, Toru Kontani and Hiroshi Suzuki

Molecules 2011, 16(9), 7210-7223; https://doi.org/10.3390/molecules16097210 - 25 Aug 2011

Cited by 27 | Viewed by 7659

Abstract

ASP2151 is a herpesvirus helicase-primase inhibitor with antiviral activity against varicella zoster virus and herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Here, we examined the potency and efficacy of ASP2151 against HSV in vitro and in vivo. We found that [...] Read more.

ASP2151 is a herpesvirus helicase-primase inhibitor with antiviral activity against varicella zoster virus and herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Here, we examined the potency and efficacy of ASP2151 against HSV in vitro and in vivo. We found that ASP2151 was more potent in inhibiting the replication of HSV-1 and HSV-2 in Vero cells in the plaque reduction assay and had greater anti-HSV activity in a guinea pig model of genital herpes than did acyclovir and valacyclovir (VACV), respectively. Oral ASP2151 given from the day of infection reduced peak and overall disease scores in a dose-dependent manner, resulting in complete prevention of symptoms at the dose of 30 mg/kg. The 50% effective dose (ED₅₀) values for ASP2151 and VACV were 0.37 and 68 mg/kg, respectively, indicating that ASP2151 was 184-fold more potent than VACV. When ASP2151 was administered after the onset of symptoms, the disease course of genital herpes was suppressed more effectively than by VACV, with a significant reduction in disease score observed one day after starting ASP2151 at 30 mg/kg, whereas the therapeutic effect of VACV was only evident three days after treatment at the highest dose tested (300 mg/kg). This indicated that ASP2151 possesses a faster onset of action and wider therapeutic time window than VACV. Further, virus shedding from the genital mucosa was significantly reduced with ASP2151 at 10 and 30 mg/kg but not with VACV, even at 300 mg/kg. Taken together, our present findings demonstrated the superior potency and efficacy of ASP2151 against HSV. Full article

(This article belongs to the Special Issue Antivirals)

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1056 KiB

Open AccessArticle

Anti-Inflammatory Effect of Myristicin on RAW 264.7 Macrophages Stimulated with Polyinosinic-Polycytidylic Acid

by Ji Young Lee and Wansu Park

Molecules 2011, 16(8), 7132-7142; https://doi.org/10.3390/molecules16087132 - 22 Aug 2011

Cited by 100 | Viewed by 12024

Abstract

Myristicin (1-allyl-5-methoxy-3,4-methylenedioxybenzene) is an active aromatic compound found in nutmeg (the seed of Myristica fragrans), carrot, basil, cinnamon, and parsley. Myristicin has been known to have anti-cholinergic, antibacterial, and hepatoprotective effects, however, the effects of myristicin on virus-stimulated macrophages are not fully [...] Read more.

Myristicin (1-allyl-5-methoxy-3,4-methylenedioxybenzene) is an active aromatic compound found in nutmeg (the seed of Myristica fragrans), carrot, basil, cinnamon, and parsley. Myristicin has been known to have anti-cholinergic, antibacterial, and hepatoprotective effects, however, the effects of myristicin on virus-stimulated macrophages are not fully reported. In this study, the anti-inflammatory effect of myristicin on double-stranded RNA (dsRNA)-stimulated macrophages was examined. Myristicin did not reduce the cell viability of RAW 264.7 mouse macrophages at concentrations of up to 50 µM. Myristicin significantly inhibited the production of calcium, nitric oxide (NO), interleukin (IL)-6, IL-10, interferon inducible protein-10, monocyte chemotactic protein (MCP)-1, MCP-3, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein (MIP)-1α, MIP-1β, and leukemia inhibitory factor in dsRNA [polyinosinic-polycytidylic acid]-induced RAW 264.7 cells (P < 0.05). In conclusion, myristicin has anti-inflammatory properties related with its inhibition of NO, cytokines, chemokines, and growth factors in dsRNA-stimulated macrophages via the calcium pathway. Full article

(This article belongs to the Special Issue Antivirals)

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453 KiB

Open AccessArticle

Antiviral Properties of Lactoferrin—A Natural Immunity Molecule

by Francesca Berlutti, Fabrizio Pantanella, Tiziana Natalizi, Alessandra Frioni, Rosalba Paesano, Antonella Polimeni and Piera Valenti

Molecules 2011, 16(8), 6992-7018; https://doi.org/10.3390/molecules16086992 - 16 Aug 2011

Cited by 245 | Viewed by 19478

Abstract

Lactoferrin, a multifunctional iron binding glycoprotein, plays an important role in immune regulation and defence mechanisms against bacteria, fungi and viruses. Lactoferrin’s iron withholding ability is related to inhibition of microbial growth as well as to modulation of motility, aggregation and biofilm formation [...] Read more.

Lactoferrin, a multifunctional iron binding glycoprotein, plays an important role in immune regulation and defence mechanisms against bacteria, fungi and viruses. Lactoferrin’s iron withholding ability is related to inhibition of microbial growth as well as to modulation of motility, aggregation and biofilm formation of pathogenic bacteria. Independently of iron binding capability, lactoferrin interacts with microbial, viral and cell surfaces thus inhibiting microbial and viral adhesion and entry into host cells. Lactoferrin can be considered not only a primary defense factor against mucosal infections, but also a polyvalent regulator which interacts in viral infectious processes. Its antiviral activity, demonstrated against both enveloped and naked viruses, lies in the early phase of infection, thus preventing entry of virus in the host cell. This activity is exerted by binding to heparan sulphate glycosaminoglycan cell receptors, or viral particles or both. Despite the antiviral effect of lactoferrin, widely demonstrated in vitro studies, few clinical trials have been carried out and the related mechanism of action is still under debate. The nuclear localization of lactoferrin in different epithelial human cells suggests that lactoferrin exerts its antiviral effect not only in the early phase of surface interaction virus-cell, but also intracellularly. The capability of lactoferrin to exert a potent antiviral activity, through its binding to host cells and/or viral particles, and its nuclear localization strengthens the idea that lactoferrin is an important brick in the mucosal wall, effective against viral attacks and it could be usefully applied as novel strategy for treatment of viral infections. Full article

(This article belongs to the Special Issue Antivirals)

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1284 KiB

Open AccessArticle

Benzylidene-bis-(4-Hydroxycoumarin) and Benzopyrano-Coumarin Derivatives: Synthesis, ¹H/¹³C-NMR Conformational and X-ray Crystal Structure Studies and In Vitro Antiviral Activity Evaluations

by Davorka Završnik, Samija Muratović, Damjan Makuc, Janez Plavec, Mario Cetina, Ante Nagl, Erik De Clercq, Jan Balzarini and Mladen Mintas

Molecules 2011, 16(7), 6023-6040; https://doi.org/10.3390/molecules16076023 - 19 Jul 2011

Cited by 88 | Viewed by 12090

Abstract

We report on the synthesis of 4-hydroxycoumarin dimers 1–15 bearing an aryl substituent on the central linker and fused benzopyranocoumarin derivatives 16–20 and on their in vitro broad anti-DNA and RNA virus activity evaluations. The chemical identities and structure [...] Read more.

We report on the synthesis of 4-hydroxycoumarin dimers 1–15 bearing an aryl substituent on the central linker and fused benzopyranocoumarin derivatives 16–20 and on their in vitro broad anti-DNA and RNA virus activity evaluations. The chemical identities and structure of compounds 1–20 were deduced from their homo- and heteronuclear NMR measurements whereas the conformational properties of 5, 14 and 20 were assessed by the use of 1D difference NOE enhancements. Unequivocal proof of the stereostructure of compounds 7, 9, 16 and 18 was obtained by single crystal X-ray diffraction method. The X-ray crystal structure analysis revealed that two 4-hydroxycoumarin moieties in the 4-trifluoromethylphenyl- and 2-nitrophenyl derivatives (compounds 7 and 9, respectively) are intramolecularly hydrogen-bonded between hydroxyl and carbonyl oxygen atoms. Consequently, the compounds 7 and 9 adopt conformations in which two 4-hydroxy-coumarin moieties are anti-disposed. Antiviral activity evaluation results indicated that the 4-bromobenzylidene derivative of bis-(4-hydroxycoumarin) (compound 3) possesses inhibitory activity against HSV-1 (KOS), HSV-2 (G), vaccinia virus and HSV-1 TK^- KOS (ACV^r) at a concentration of 9–12 μM and at a minimum cytotoxic concentration (MCC) greater than 20 μM. Compounds 4–6, 8, and 20 were active against feline herpes virus (50% effective concentration, EC₅₀ = 5–8.1 μM), that is at a 4-7-fold lower concentration than the MCC. Full article

(This article belongs to the Special Issue Antivirals)

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468 KiB

Open AccessArticle

Mangiferin, an Anti-HIV-1 Agent Targeting Protease and Effective against Resistant Strains

by Rui-Rui Wang, Yue-Dong Gao, Chun-Hui Ma, Xing-Jie Zhang, Cheng-Gang Huang, Jing-Fei Huang and Yong-Tang Zheng

Molecules 2011, 16(5), 4264-4277; https://doi.org/10.3390/molecules16054264 - 24 May 2011

Cited by 61 | Viewed by 10875

Abstract

The anti-HIV-1 activity of mangiferin was evaluated. Mangiferin can inhibit HIV-1_Ⅲ_B induced syncytium formation at non-cytotoxic concentrations, with a 50% effective concentration (EC₅₀) at 16.90 μM and a therapeutic index (TI) above 140. Mangiferin also showed good activities in [...] Read more.

The anti-HIV-1 activity of mangiferin was evaluated. Mangiferin can inhibit HIV-1_Ⅲ_B induced syncytium formation at non-cytotoxic concentrations, with a 50% effective concentration (EC₅₀) at 16.90 μM and a therapeutic index (TI) above 140. Mangiferin also showed good activities in other laboratory-derived strains, clinically isolated strains and resistant HIV-1 strains. Mechanism studies revealed that mangiferin might inhibit the HIV-1 protease, but is still effective against HIV peptidic protease inhibitor resistant strains. A combination of docking and pharmacophore methods clarified possible binding modes of mangiferin in the HIV-1 protease. The pharmacophore model of mangiferin consists of two hydrogen bond donors and two hydrogen bond acceptors. Compared to pharmacophore features found in commercially available drugs, three pharmacophoric elements matched well and one novel pharmacophore element was observed. Moreover, molecular docking analysis demonstrated that the pharmacophoric elements play important roles in binding HIV-1 protease. Mangiferin is a novel nonpeptidic protease inhibitor with an original structure that represents an effective drug development strategy for combating drug resistance. Full article

(This article belongs to the Special Issue Antivirals)

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1311 KiB

Open AccessArticle

Identification and Characterization of Three Novel Small Interference RNAs That Effectively Down-Regulate the Isolated Nucleocapsid Gene Expression of SARS Coronavirus

by Ying-Li Cao, Ying Wang, Rong Guo, Fan Yang, Yun Zhang, Shu-Hui Wang and Li Liu

Molecules 2011, 16(2), 1544-1558; https://doi.org/10.3390/molecules16021544 - 11 Feb 2011

Cited by 5 | Viewed by 9798

Abstract

Nucleocapsid (N) protein of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is a major pathological determinant in the host that may cause host cell apoptosis, upregulate the proinflammatory cytokine production, and block innate immune responses. Therefore, N gene has long been thought an ideal [...] Read more.

Nucleocapsid (N) protein of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is a major pathological determinant in the host that may cause host cell apoptosis, upregulate the proinflammatory cytokine production, and block innate immune responses. Therefore, N gene has long been thought an ideal target for the design of small interference RNA (siRNA). siRNA is a class of small non-coding RNAs with a size of 21-25nt that functions post-transcriptionally to block targeted gene expression. In this study, we analyzed the N gene coding sequences derived from 16 different isolates, and found that nucleotide deletions and substitutions are mainly located at the first 440nt sequence. Combining previous reports and the above sequence information, we create three novel siRNAs that specifically target the conserved and unexploited regions in the N gene. We show that these siRNAs could effectively and specifically block the isolated N gene expression in mammal cells. Furthermore, we provide evidence to show that N gene can effectively up-regulate M gene mediated interferon b (IFNb) production, while blocking N gene expression by specific siRNA significantly reduces IFNb gene expression. Our data indicate that the inhibitory effect of siRNA on the isolated N gene expression might be influenced by the sequence context around the targeted sites. Full article

(This article belongs to the Special Issue Antivirals)

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223 KiB

Open AccessArticle

Crucial Role of Selenium in the Virucidal Activity of Benzisoselenazol-3(2H)-ones and Related Diselenides

by Magdalena Pietka-Ottlik, Piotr Potaczek, Egbert Piasecki and Jacek Mlochowski

Molecules 2010, 15(11), 8214-8228; https://doi.org/10.3390/molecules15118214 - 12 Nov 2010

Cited by 55 | Viewed by 11402

Abstract

Various N-substituted benzisoselenazol-3(2H)-ones and their non-selenium-containing analogues have been synthesized and tested against selected viruses (HHV-1, EMCV and VSV) to determine the extent to which selenium plays a role in antiviral activity. The data presented here show that the presence [...] Read more.

Various N-substituted benzisoselenazol-3(2H)-ones and their non-selenium-containing analogues have been synthesized and tested against selected viruses (HHV-1, EMCV and VSV) to determine the extent to which selenium plays a role in antiviral activity. The data presented here show that the presence of selenium is crucial for the antiviral properties of benzisoselenazol-3(2H)-ones since their isostructural analogues having different groups but lacking selenium either did not show any antiviral activity or their activity was substantially lower. The open-chain analogues of benzisoselenazol-3(2H)-ones—diselenides also exhibited high antiviral activity while selenides and disulfides were completely inactive towards model viruses. Full article

(This article belongs to the Special Issue Antivirals)

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Review

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380 KiB

Open AccessReview

Silver Nanoparticles as Potential Antiviral Agents

by Stefania Galdiero, Annarita Falanga, Mariateresa Vitiello, Marco Cantisani, Veronica Marra and Massimiliano Galdiero

Molecules 2011, 16(10), 8894-8918; https://doi.org/10.3390/molecules16108894 - 24 Oct 2011

Cited by 753 | Viewed by 39430

Abstract

Virus infections pose significant global health challenges, especially in view of the fact that the emergence of resistant viral strains and the adverse side effects associated with prolonged use continue to slow down the application of effective antiviral therapies. This makes imperative the [...] Read more.

Virus infections pose significant global health challenges, especially in view of the fact that the emergence of resistant viral strains and the adverse side effects associated with prolonged use continue to slow down the application of effective antiviral therapies. This makes imperative the need for the development of safe and potent alternatives to conventional antiviral drugs. In the present scenario, nanoscale materials have emerged as novel antiviral agents for the possibilities offered by their unique chemical and physical properties. Silver nanoparticles have mainly been studied for their antimicrobial potential against bacteria, but have also proven to be active against several types of viruses including human imunodeficiency virus, hepatitis B virus, herpes simplex virus, respiratory syncytial virus, and monkey pox virus. The use of metal nanoparticles provides an interesting opportunity for novel antiviral therapies. Since metals may attack a broad range of targets in the virus there is a lower possibility to develop resistance as compared to conventional antivirals. The present review focuses on the development of methods for the production of silver nanoparticles and on their use as antiviral therapeutics against pathogenic viruses. Full article

(This article belongs to the Special Issue Antivirals)

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998 KiB

Open AccessReview

Pharmacological and Biological Antiviral Therapeutics for Cardiac Coxsackievirus Infections

by Henry Fechner, Sandra Pinkert, Anja Geisler, Wolfgang Poller and Jens Kurreck

Molecules 2011, 16(10), 8475-8503; https://doi.org/10.3390/molecules16108475 - 11 Oct 2011

Cited by 32 | Viewed by 10027

Abstract

Subtype B coxsackieviruses (CVB) represent the most commonly identified infectious agents associated with acute and chronic myocarditis, with CVB3 being the most common variant. Damage to the heart is induced both directly by virally mediated cell destruction and indirectly due to the immune [...] Read more.

Subtype B coxsackieviruses (CVB) represent the most commonly identified infectious agents associated with acute and chronic myocarditis, with CVB3 being the most common variant. Damage to the heart is induced both directly by virally mediated cell destruction and indirectly due to the immune and autoimmune processes reacting to virus infection. This review addresses antiviral therapeutics for cardiac coxsackievirus infections discovered over the last 25 years. One group represents pharmacologically active low molecular weight substances that inhibit virus uptake by binding to the virus capsid (e.g., pleconaril) or inactivate viral proteins (e.g., NO-metoprolol and ribavirin) or inhibit cellular proteins which are essential for viral replication (e.g., ubiquitination inhibitors). A second important group of substances are interferons. They have antiviral but also immunomodulating activities. The third and most recently discovered group includes biological and cellular therapeutics. Soluble receptor analogues (e.g., sCAR-Fc) bind to the virus capsid and block virus uptake. Small interfering RNAs, short hairpin RNAs and antisense oligonucleotides bind to and led to degradation of the viral RNA genome or cellular RNAs, thereby preventing their translation and viral replication. Most recently mesenchymal stem cell transplantation has been shown to possess antiviral activity in CVB3 infections. Taken together, a number of antiviral therapeutics has been developed for the treatment of myocardial CVB infection in recent years. In addition to low molecular weight inhibitors, biological therapeutics have become promising anti-viral agents. Full article

(This article belongs to the Special Issue Antivirals)

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338 KiB

Open AccessReview

Oligomeric Nucleic Acids as Antivirals

by Alessandra Mescalchin and Tobias Restle

Molecules 2011, 16(2), 1271-1296; https://doi.org/10.3390/molecules16021271 - 28 Jan 2011

Cited by 34 | Viewed by 9207

Abstract

Based on the natural functions and chemical characteristics of nucleic acids, a variety of novel synthetic drugs and tools to explore biological systems have become available in recent years. To date, a great number of antisense oligonucleotides, RNA interference-based tools, CpG‑containing oligonucleotides, catalytic [...] Read more.

Based on the natural functions and chemical characteristics of nucleic acids, a variety of novel synthetic drugs and tools to explore biological systems have become available in recent years. To date, a great number of antisense oligonucleotides, RNA interference-based tools, CpG‑containing oligonucleotides, catalytic oligonucleotides, decoys and aptamers has been produced synthetically and applied successfully for understanding and manipulating biological processes and in clinical trials to treat a variety of diseases. Their versatility and potency make them equally suited candidates for fighting viral infections. Here, we describe the different types of nucleic acid-based antivirals, their mechanism of action, their advantages and limitations, and their future prospects. Full article

(This article belongs to the Special Issue Antivirals)

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1381 KiB

Open AccessReview

Targeting Cell Entry of Enveloped Viruses as an Antiviral Strategy

by Elodie Teissier, François Penin and Eve-Isabelle Pécheur

Molecules 2011, 16(1), 221-250; https://doi.org/10.3390/molecules16010221 - 30 Dec 2010

Cited by 76 | Viewed by 15398

Abstract

The entry of enveloped viruses into their host cells involves several successive steps, each one being amenable to therapeutic intervention. Entry inhibitors act by targeting viral and/or cellular components, through either the inhibition of protein-protein interactions within the viral envelope proteins or between [...] Read more.

The entry of enveloped viruses into their host cells involves several successive steps, each one being amenable to therapeutic intervention. Entry inhibitors act by targeting viral and/or cellular components, through either the inhibition of protein-protein interactions within the viral envelope proteins or between viral proteins and host cell receptors, or through the inhibition of protein-lipid interactions. Interestingly, inhibitors that concentrate into/onto the membrane in order to target a protein involved in the entry process, such as arbidol or peptide inhibitors of the human immunodeficiency virus (HIV), could allow the use of doses compatible with therapeutic requirements. The efficacy of these drugs validates entry as a point of intervention in viral life cycles. Strategies based upon small molecule antiviral agents, peptides, proteins or nucleic acids, would most likely prove efficient in multidrug combinations, in order to inhibit several steps of virus life cycle and prevent disease progression. Full article

(This article belongs to the Special Issue Antivirals)

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