Antiviral effect of octyl gallate against DNA and RNA viruses

The effects of gallic acid (3,4,5-trihydroxybenzoic acid) and its alkyl esters on virus growth and virion infectivity were examined. All the compounds tested showed an inhibitory effect on the growth of herpes simplex virus type 1 (HSV-1) in HEp-2 or Vero cells. The antiviral activity of gallic acid alkyl esters was enhanced by increasing the number of carbon in the alkyl moieties of the compounds, reaching maximum at a carbon number of 12 (lauryl gallate), but both cytocidal activity and cytopathic effect of the compounds were also significantly increased simultaneously. Among these compounds, octyl gallate showed a marked antiviral effect with a relatively moderate cytotoxity. In addition, octyl gallate suppressed the multiplication of RNA viruses, such as vesicular stomatitis virus and poliovirus. Quantitative characterization of the HSV-1 infection in the presence of octyl gallate revealed that: (1) this reagent can directly inactivate HSV-1 (virucidal activity), (2) it suppresses both the intracellar multiplication and the release of the virus, (3) it selectively accelerates death of the virus-infected cells and (4) the addition of the reagent even at 6-h post infection completely abolishes the formation of progeny virus in the infected cells.     

Patent Evaluation: Antiviral agents against retroviruses,and DNA and RNA viruses

Novelty: Novel antiviral compounds useful for preventing and treating infections caused by a variety of DNA viruses, RNA viruses and retroviruses are disclosed.

Biology: The pharmacological efficacy of the compounds were tested in vitro and in vivo for HSV-I activity and cytotoxicity. The results are presented in five tables. The compounds have strong activities and low toxicities.

Chemistry: Preparation of the antiviral agents are described in four examples. 1 -Phenylpiper-azine is one of twenty-three specifically claimed compounds.     

Antiviral activity of some beta-diketones. 2. Aryloxy alkyl diketones. In vitro activity against both RNA and DNA viruses.

A series of aryloxy alkyl diketones II was synthesized and screened in vitro for antiviral activity. The effect of various substituents on the phenyl ring, as well as the length of the alkyl bridge, was examined to establish the requirements for optimum activity. One of the most active members of the series, 4-[6-(2-chloro-4-methoxy)phenoxy]hexyl-3,5-heptanedione (56), exhibited a high level of activity against both DNA and RNA viruses in both the tissue culture and organ culture screens and was particularly effective against herpesvirus type 1 and 2.     

Antiviral activity of some beta-diketones. 1. Aryl alkyl diketones. In vitro activity against both RNA and DNA viruses.

The discovery that 4-[3-ethyl-6-[(3,4-methylenedioxy)phenyl]-3-hexenyl]-3,5-heptanedione (40) exhibited an in vitro inhibitory effect against equine rhinovirus led to a structure--activity study to establish the criteria for optimum activity. Modification of the bridge included removal of the ethyl group and reduction of the double bond. The heptanedione was replaced with hexanedione and pentanedione with a minimal effect. The effect of replacing the heptanedione with beta-keto esters and monoketones was also investigated. Maintaining the hexamethylene bridge and heptanedione, the methylenedioxy group was replaced with various substitutents. In general, most substituents did not adversely affect activity particularly against equine rhinovirus although there was some variation in activity against herpesvirus. Strongly hydrophilic groups significantly reduced activity. Finally, the effect of varying the length of the alkyl bridge was examined in the 4-hydroxyphenyl series, where peak activity was attained with n = 8.     

Antiviral activity of S-adenosylhomocysteine hydrolase inhibitors against plant viruses

Three SAH hydrolase inhibitors, (RS)-3-adenin-9-yl-2-hydroxypropanoic acid (isobutyl ester) [(RS)-AHPA]; (RS)-9-(2,3-dihydroxypropyl)adenine [(RS)-DHPA] and the carbocyclic analog of 3-deazaadenosine (C-c3Ado) were evaluated for their inhibitory activity against tobacco mosaic virus (TMV) and potato virus X (PVX). Using the local lesion assay and ELISA, we demonstrated that all three compounds inhibit the replication of TMV and PVX. Whereas the three compounds proved about equally active against PVX, (RS)-AHPA was the most effective against TMV. (RS)-AHPA and C-c3Ado induced chlorosis in Nicotiana tabacum leaf discs. They also caused a substantial reduction in the growth of the main root of Phaseolus vulgaris. (RS)-DHPA was less phytotoxic than its two congeners.     

Virucidal activity of hypericin against enveloped and non-enveloped DNA and RNA viruses.

Hypericin is a polycyclic anthrone first isolated from the plant St. Johnswort and was shown to have dramatic anti-retroviral activity against Friend leukemia virus and radiation leukemia virus in mice. Hypericin displayed marginal activity (IC50 = 6 micrograms/ml) against Moloney murine leukemia virus (Mo-MuLV) in vitro. Hypericin did not display selective antiviral activity against herpes simplex virus, influenza A, adenovirus, or poliovirus. The 50% cytotoxic concentration was approximately 25 micrograms/ml. When virus was incubated with hypericin before infecting cells, the drug was virucidal to all enveloped viruses tested (herpes simplex, influenza virus A, and Mo-MuLV) at concentrations of 1.56 micrograms/ml to 25 micrograms/ml. Hypericin was not virucidal to the non-enveloped viruses tested (adenovirus and poliovirus). These data indicate that the mechanism of viral inactivation for hypericin is dependent upon the presence of a viral lipid envelope. In vivo, hypericin (50 mg/ml) was effective against FLV or HSV-1 if incubated with the virus for 1 h at 37 degrees C before infecting mice, but was not effective if pre-incubated with virus for 1 h at 4 degrees C or if administered concurrently with virus.     

Antiviral activity and its mechanism of guanine 7-N-oxide on DNA and RNA viruses derived from salmonid

Guanine 7-N-oxide produced by Streptomyces sp. was found to inhibit in vitro the replication of herpes virus (Oncorhynchus masou virus, OMV), rhabdo virus (infectious hematopoietic necrosis virus, IHNV) and a bi-segmented double-strand virus (infectious pancreatic necrosis virus, IPNV) derived from salmonids with IC50 values of about 10 micrograms/ml, 20 micrograms/ml and 32 micrograms/ml, respectively. The agent was not toxic for the host cells (chinook salmon embryo, CHSE-214) at the IC50 concentrations. Labeling of IHNV viral RNA and host cellular DNA and RNA with [3H]uridine and [3H]thymidine during drug treatment showed that guanine 7-N-oxide did not reduce the incorporation of these precusors into RNA and DNA. The anti-IHNV activity of guanine 7-N-oxide was enhanced synergistically by neplanocin A, an inhibitor of RNA methylation. The mechanism of action of guanine 7-N-oxide is discussed, in regard to maturation of viral messenger RNA including capping.     

Antiviral activity of Aloe hijazensis against some haemagglutinating viruses infection and its phytoconstituents

Evaluation of the antiviral activities of flowers, flower-peduncles, leaves, and roots of Aloe hijazensis against haemagglutinating viruses of avian paramyxovirus type-1 (APMV-1), avian influenza virus type A (AI-H5N1), Newcastle disease virus (NDV), and egg-drop syndrome virus (EDSV) in specific pathogen free (SPF) chicken embryos were carried out. Extract of the flowers and leaves showed relatively higher activity than the extracts of other plant parts. Thirteen compounds were isolated from both the flowers and flower-peduncles of A. hijazensis. The isolated compounds were classified into: five anthraquinones; ziganein, ziganein-5-methyl ether, aloesaponarin I, chrysophanol, aloe-emodin, one dihydroisocoumarin; feralolide, four flavonoids; homoplantaginin, isoorientin, luteolin 7-glucuronopyranoside, isovitexin, one phenolic acid; p-coumaric acid, the anthrone; barbaloin together with aloenin. Eleven compounds were attributed to the flowers and seven to the flower-peduncles. Homoplantaginin and luteolin 7-glucuronopyranoside are reported here for the first time from Aloe spp. To the best of our knowledge, this is the first report on the chemical composition and biological activity of those plant parts.     

Antiviral activity of the proteasome inhibitor VL-01 against influenza A viruses

The appearance of highly pathogenic avian influenza A viruses of the H5N1 subtype being able to infect humans and the 2009 H1N1 pandemic reveals the urgent need for new and efficient countermeasures against these viruses. The long-term efficacy of current antivirals is often limited, because of the emergence of drug-resistant virus mutants. A growing understanding of the virus-host interaction raises the possibility to explore alternative targets involved in the viral replication. In the present study we show that the proteasome inhibitor VL-01 leads to reduction of influenza virus replication in human lung adenocarcinoma epithelial cells (A549) as demonstrated with three different influenza virus strains, A/Puerto Rico/8/34 (H1N1) (EC₅₀ value of 1.7 μM), A/Regensburg/D6/09 (H1N1v) (EC₅₀ value of 2.4 μM) and A/Mallard/Bavaria/1/2006 (H5N1) (EC₅₀ value of 0.8 μM). In in vivo experiments we could demonstrate that VL-01-aerosol-treatment of BALB/c mice with 14.1 mg/kg results in no toxic side effects, reduced progeny virus titers in the lung (1.1 ± 0.3 log₁₀ pfu) and enhanced survival of mice after infection with a 5-fold MLD₅₀ of the human influenza A virus strain A/Puerto Rico/8/34 (H1N1) up to 50%. Furthermore, treatment of mice with VL-01 reduced the cytokine release of IL-α/β, IL-6, MIP-1β, RANTES and TNF-α induced by LPS or highly pathogen avian H5N1 influenza A virus. The present data demonstrates an antiviral effect of VL-01 in vitro and in vivo and the ability to reduce influenza virus induced cytokines and chemokines.     

Antiviral activity of cyclosaligenyl prodrugs of the nucleoside analogue bromovinyldeoxyuridine against herpes viruses

A series of 42 lipophilic bromovinyldeoxyuridine monophosphates (BVDUMPs) are presented as potential prodrugs of the antiviral agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU). The 5'-cycloSal-masking group technique has been applied to this cyclic nucleoside analogue to achieve delivery of the monophosphate of BVDU inside the target cells. The new substances have been tested for their antiviral activity against herpes simplex virus types 1 and 2 (HSV-1 and -2), thymidine kinase-deficient (TK(-)) HSV-1, varicella-zoster virus (VZV), human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV). The XTT-based tetrazolium reduction assay EZ4U (for HSV), the plaque inhibition test (for VZV and HCMV) and a DNA hybridisation assay (for EBV) were used to assess antiviral activity. The results indicate that cycloSal-BVDUMP triesters proved to be potent and selective inhibitors of HSV-1 comparable with aciclovir. VZV replication was inhibited by very low concentrations, and two substances had a slightly better anti-VZV activity than the parent compound BVDU. No antiviral effect could be demonstrated against TK(-)-HSV-1, HSV-2 and HCMV, most likely owing to the lack of phosphorylation to BVDU diphosphate. Most remarkably, several cycloSal-BVDUMP triesters yielded promising anti-EBV activity whereas the parent compound BVDU was entirely inactive.     

Antiviral agents active against influenza A viruses

The recent outbreaks of avian influenza A (H5N1) virus, its expanding geographic distribution and its ability to transfer to humans and cause severe infection have raised serious concerns about the measures available to control an avian or human pandemic of influenza A. In anticipation of such a pandemic, several preventive and therapeutic strategies have been proposed, including the stockpiling of antiviral drugs, in particular the neuraminidase inhibitors oseltamivir (Tamiflu; Roche) and zanamivir (Relenza; GlaxoSmithKline). This article reviews agents that have been shown to have activity against influenza A viruses and discusses their therapeutic potential, and also describes emerging strategies for targeting these viruses.     

小儿宝泰康颗粒对呼吸道病毒感染的抗病毒作用研究

目的 观察小儿宝泰康颗粒对呼吸道合胞病毒和腺病毒感染细胞的抑制作用,以便为呼吸道病毒感染的治疗提供新的药物。方法 通过细胞培养技术观察不同浓度的小儿宝泰康颗粒对HEp-2细胞的细胞毒作用,采用MTT法并结合CPE法检测病毒感染细胞存活率和病毒抑制率,以利巴韦林作为阳性药物对照,评价该药物对呼吸道合胞病毒和腺病毒感染细胞的抗病毒活性。结果 小儿宝泰康颗粒对HEp-2细胞的半数细胞毒性浓度（TC₅₀）为4.4 mg·mL^-1,对呼吸道合胞病毒的半数有效浓度（EC₅₀）为2.03 mg·mL^-1,而腺病毒的EC₅₀为0.65 mg·mL^-1,抗病毒指数分别为2.17和6.75。在对两种病毒的直接灭活作用中,EC₅₀分别为4.13和8.99 mg·mL^-1。阳性对照药物病毒唑在128 g·mL^-1时,对呼吸道合胞病毒和腺病毒的抑制率分别为92.7%和80.16%。结论 小儿宝泰康颗粒是一种对呼吸道合胞病毒和腺病毒感染有抗病毒作用的药物,有临床应用前景和进一步研究的价值。     

Antiviral efficacy of pyrazofurin against selected rna viruses

The antibiotic pyrazofurin, 3-(β-D-ribofuranosyl)-4-hydroxypyrazole-5-carboxamide, markedly inhibited the in vitro replication of a number of RNA viruses including Rift Valley fever (RVF), Venezuelan equine encephalomyelitis (VEE), Sandfly, Pichinde, Lassa and LCM virus. Plaque formation was reduced by 80% or more with 2–10 μg/ml of pyrazofurin while 2 μg/ml reduced by 1000-fold the yield of Lassa and LCM virus in a yield reduction assay. In vivo, pyrazofurin failed to protect mice and guinea pigs against a lethal challenge with VEE and Pichinde virus, respectively. On the other hand, pyrazofurin caused a slight increase in the mean time to death of mice infected with RVF virus.     

The host-targeting compound peruvoside has a broad-spectrum antiviral activity against positive-sense RNA viruses

Positive-sense RNA viruses modify intracellular calcium stores, endoplasmic reticulum and Golgi apparatus(Golgi) to generate membranous replication organelles known as viral factories. Viral factories provide a conducive and substantial enclave for essential virus replication via concentrating necessary cellular factors and viral proteins in proximity. Here, we identified the vital role of a broadspectrum antiviral, peruvoside in limiting the formation of viral factories. Mechanistically, we rev...     

Antiviral action of lysolecithin analogs against human pathogenic viruses

The virucidal effect, the inhibition of virus adsorption and penetration and the influence on later phases of replication of human pathogenic viruses were studied. The compounds showed a significant virucidal effect to enveloped viruses (measles virus, herpes virus type 1 and 2), whereas the compounds were ineffective against nonenveloped viruses (Coxsackie virus A9 and B1, attenuated poliovirus type 1, adenovirus type 1). Interactions with the viral envelope are supposed.     

细胞基因工程重组人α_1干扰素对7种流感病毒的抗病毒作用

目的:研究细胞基因工程人α干扰素(rhIFN-α_1)对体外7种流感病毒感染的MDCK细胞以及对甲型流感病毒鼠肺适应株PR_8引起的小鼠肺炎的对抗作用。方法:接种7种病毒液(H_1N_1,H_2N_2,H_3N_3,B型,C型,A_1,B分离株)于MDCK细胞中,小鼠用PR_8病毒液滴鼻,观察rhIFN-α_1的抗病毒作用。结果:rhIFN-α_1对7种病毒液的最小有效浓度分别为12.5,25,50,25,12.5,25和12.5kU·L~(-1);在MDCK细胞上对7种病毒液的感染治疗指数为8×10~3,4×10~3,2×10~3,4×10~3,8×10~3,4×10~3和8×10~3;抑制指数为3.6,4.7,3.5,3.3,3.9,4.6和3.5 ;rhIFN-α_1能有效地抑制流感病毒的细胞内复制,却不能直接杀伤病毒;rhIFN-α_1对小鼠病毒肺炎有抑制作用,使肺组织炎症,纤维间质增生明显改善,降低病毒滴度,延长生命率为94.2％-132.7％,肺指数抑制率为14.8％-37.4％。结论:rhIFN-α_1对流感病毒的增殖有抑制作用,并且能够改善流感病毒引起的小鼠肺炎症状。