scholarly journals RELATIONSHIP BETWEEN STRUCTURE OF BENZIMIDAZOLE DERIVATIVES AND SELECTIVE VIRUS INHIBITORY ACTIVITY

1961 ◽  
Vol 113 (4) ◽  
pp. 625-656 ◽  
Author(s):  
Igor Tamm ◽  
Rostom Bablanian ◽  
Marjorie M. Nemes ◽  
Clifford H. Shunk ◽  
Franklin M. Robinson ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Cell Damage ◽  
Chorioallantoic Membrane ◽  
Virus Multiplication ◽  
Influenza B Virus ◽  
Influenza B ◽  
Cytopathic Effects ◽  
B Virus

The virus inhibitory activity and selectivity of certain benzimidazole, benzotriazole, and naphthimidazole derivatives were determined with influenza B and polio type 2 viruses. Among the sixty-five compounds examined, several were highly active inhibitors of influenza B virus multiplication in the chorioallantoic membrane in vitro. The following compounds, listed in order of increasing inhibitory activity, were more than 100 times as active as benzimidazole: 5-(4'-toluenesulfonamido)-benzimidazole, 5-hydroxybenzotriazole-4-carboxy-α-naphthylamide, 4,5,6-trichlorobenzotriazole, 5-(3',4'-dichlorobenzenesulfonamido)-benzimidazole, 5-(3',4'-dichlorobenzenesulfonamido) - 1 - (3'',4'' - dichlorobenzenesulfonyl)-benzimidazole, 4-(p-chlorophenylazo)-5-hydroxybenzotriazole, and 4,5,6,7-tetrachlorobenzotriazole. However, none showed high selectivity. Of the sixty-five compounds studied with influenza virus, twenty-five were also examined with poliovirus type 2 in monkey kidney cells in vitro. Included in this group were five of the seven most active inhibitors of influenza virus, listed above. All five were more than 100 times as active in inhibiting poliovirus multiplication as the reference compound. In addition to these, two other compounds were highly active: 2-(α-hydroxybenzyl)-benzimidazole (HBB), and 2-(α-hydroxybenzyl)-5-chlorobenzimidazole, with relative inhibitory activities of 78 and 130, respectively. These two compounds, and the much less active 5,6-dichloro derivative of HBB, were the only ones which showed no, or only slight, toxic effects on cells at concentrations sufficient to cause considerable inhibition of poliovirus multiplication. Furthermore, HBB and the 5-chloro derivative were the only compounds which caused significant inhibition of the cytopathic effects of poliovirus. HBB, and its 5-chloro and 5,6-dichloro derivatives had no effect on the multiplication of influenza B virus in the chorioallantoic membrane. In addition, HBB failed to inhibit influenza B virus multiplication and cytopathic effects in monkey kidney cells. Inhibition of poliovirus-induced cell damage by HBB was characterized by the following features: the curves relating reduction in virus yield or cytopathic effects to concentration of the compound followed an approximately parallel course; somewhat higher concentrations were required to inhibit virus-induced cell damage than to reduce virus yield. HBB suppressed viral cytopathic effects for a period of time which varied directly with the concentration of compound, and inversely with the size of virus inoculum. The development of virus-induced cell damage in treated cultures on prolonged incubation was not due to inactivation of HBB. The inhibitory effect of HBB on virus-induced cell damage was reversible by removal of the compound. HBB inhibited viral cytopathic effects when given during the exponential increase phase in virus multiplication. Inhibition of virus-induced cell damage by HBB was demonstrated by photomicrographs. HBB did not inactivate the infectivity of poliovirus type 2.

scholarly journals INHIBITION OF INFLUENZA VIRUS MULTIPLICATION BY ALKYL DERIVATIVES OF BENZIMIDAZOLE

1953 ◽  
Vol 98 (3) ◽  
pp. 229-243 ◽  
Author(s):  
Igor Tamm ◽  
Karl Folkers ◽  
Frank L. Horsfall
Keyword(s):  
Influenza Virus ◽  
Culture Medium ◽  
Chorioallantoic Membrane ◽  
Virus Multiplication ◽  
Influenza B Virus ◽  
Influenza B ◽  
Experimental Conditions ◽  
Virus Reproduction ◽  
B Virus

The activity of compounds which inhibit the multiplication of influenza virus can be measured in chorioallantoic membrane cultures in vitro by means of hemagglutination titrations on the medium. Studies on the reproducibility of virus reproduction in membrane cultures have revealed the major variables which affect the results and thus have led to the development of a precise technique. Under strictly controlled experimental conditions, the extent of reproduction of the virus in membrane cultures is predictable within narrow limits of variation. With 105.5 EID50 of influenza B virus, Lee strain, and 5.75 cm.2 of chorioallantoic membrane per ml., the ratio of infective virus particles to susceptible allantoic cells appears to be approximately 1:28. Under these conditions, the evidence indicates that two cycles of multiplication occur and nearly maximal hemagglutination titers are found with culture medium at 36 hours. The extent of the deviation in the absolute titer in different experiments was only 0.112 log unit. At a concentration of 0.0017 M, 2,5-dimethylbenzimidazole caused inhibition of the multiplication of influenza B virus, Lee strain, which persisted for at least 70 hours as measured by hemagglutination titrations on the culture medium. The degree of inhibition was closely comparable to that demonstrated by infectivity titrations on the membrane at the end of the first cycle of virus reproduction (1).

scholarly journals INHIBITION OF INFLUENZA VIRUS MULTIPLICATION BY ALKYL DERIVATIVES OF BENZIMIDAZOLE

1953 ◽  
Vol 98 (3) ◽  
pp. 219-227 ◽  
Author(s):  
Igor Tamm ◽  
Karl Folkers ◽  
Frank L. Horsfall
Keyword(s):  
Influenza Virus ◽  
Latent Period ◽  
Chorioallantoic Membrane ◽  
Virus Multiplication ◽  
Influenza B Virus ◽  
Influenza B ◽  
In Ovo ◽  
Alkyl Derivatives ◽  
Rate Of Increase

At a concentration of 0.0026 M, 2,5-dimethylbenzimidazole caused a number of alterations in the first cycle of multiplication of influenza B virus, Lee strain, in chorioallantoic membrane cultures in vitro. As determined by infectivity titrations in ovo on the membrane per se, the following alterations were observed: The duration of the latent period was increased by 80 per cent. The rate of increase in titer during the incremental period was somewhat decreased. The yield of virus was decreased by about 99 per cent. When the compound was added to membrane cultures at various periods before or after inoculation with the virus, the following findings were obtained: On addition before or along with the virus, the substance caused about 99 per cent inhibition of multiplication. When added during the first 2 hours after inoculation, the compound caused inhibition of a degree which was inversely proportional to the time of addition. When added 3 to 8 hours after inoculation, the substance caused about 80 per cent inhibition. When added after the end of the latent period, no definite inhibition was obtained in the first cycle of multiplication. These results are interpreted as indicating that 2,5-dimethylbenzimidazole acts by reducing the rate of biosynthetic mechanisms necessary for the reproduction of influenza virus particles.

scholarly journals INHIBITION OF INFLUENZA VIRUS MULTIPLICATION BY ALKYL DERIVATIVES OF BENZIMIDAZOLE

1953 ◽  
Vol 98 (3) ◽  
pp. 245-259 ◽  
Author(s):  
Igor Tamm ◽  
Karl Folkers ◽  
Clifford H. Shunk ◽  
Dorothea Heyl ◽  
Frank L. Horsfall
Keyword(s):  
Influenza Virus ◽  
Inhibitory Activity ◽  
Imidazole Ring ◽  
Virus Multiplication ◽  
Influenza B Virus ◽  
Influenza B ◽  
Active Compounds ◽  
Alkyl Derivatives ◽  
Derivatives Of

The degree of inhibition of multiplication of influenza B virus, Lee strain, in membrane cultures in vitro appears to be directly related to the concentration of the inhibitory compounds used in this investigation. With each of the alkyl derivatives of benzimidazole, evidence for such a relationship was obtained in the range between 60 and 90 per cent inhibition of virus multiplication. Alteration of the structure of benzimidazole by substitution of alkyl radicals at various positions in either the benzene or the imidazole ring resulted in diverse differences in the capacity to inhibit influenza virus multiplication in vitro. Minor increases in inhibitory activity resulted when one to three methyl groups were introduced at certain positions in the molecule. Marked increases in inhibitory activity were achieved by more extensive substitution in either the benzene or the imidazole ring. The position and nature of substituent groups appeared to be of decisive importance. Among the more highly active compounds were 2,4,5,6,7-pentamethyl-benzimidazole, 5,6-diethylbenzimidazole, and 2-ethyl-5-methylbenzimidazole. Further extension of the alkyl chain at position 2 caused no significant change in the inhibitory activity of the derivative. The most active compounds studied caused 75 per cent inhibition of Lee virus multiplication in membrane cultures in vitro at concentrations of approximately 0.0002 M. Some of the implications of these findings are discussed.

scholarly journals Influenza B Virus NS1-Truncated Mutants: Live-Attenuated Vaccine Approach

2008 ◽  
Vol 82 (21) ◽  
pp. 10580-10590 ◽  
Author(s):  
Rong Hai ◽  
Luis Martínez-Sobrido ◽  
Kathryn A. Fraser ◽  
Juan Ayllon ◽  
Adolfo García-Sastre ◽  
...  
Keyword(s):  
Reverse Genetics ◽  
Influenza Viruses ◽  
Influenza B Virus ◽  
Influenza B ◽  
Type I ◽  
Live Attenuated Vaccine ◽  
Live Virus ◽  
B Virus

ABSTRACT Type B influenza viruses can cause substantial morbidity and mortality in the population, and vaccination remains by far the best means of protection against infections with these viruses. Here, we report the construction of mutant influenza B viruses for potential use as improved live-virus vaccine candidates. Employing reverse genetics, we altered the NS1 gene, which encodes a type I interferon (IFN) antagonist. The resulting NS1 mutant viruses induced IFN and, as a consequence, were found to be attenuated in vitro and in vivo. The absence of pathogenicity of the NS1 mutants in both BALB/c and C57BL/6 PKR−/− mice was confirmed. We also provide evidence that influenza B virus NS1 mutants induce a self-adjuvanted immune response and confer effective protection against challenge with both homologous and heterologous B virus strains in mice.

Assessment of the antiviral properties of recombinant surfactant protein D against influenza B virus in vitro

2015 ◽  
Vol 195 ◽  
pp. 43-46 ◽  
Author(s):  
Marine L.B. Hillaire ◽  
Martin van Eijk ◽  
Stella E. Vogelzang-van Trierum ◽  
Nella J. Nieuwkoop ◽  
Debby van Riel ◽  
...  
Keyword(s):  
Surfactant Protein ◽  
Influenza B Virus ◽  
Surfactant Protein D ◽  
Influenza B ◽  
B Virus

scholarly journals FluB-RAM and FluB-RANS: Genome Rearrangement as Safe and Efficacious Live Attenuated Influenza B Virus Vaccines

Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 897
Author(s):  
Stivalis Cardenas-Garcia ◽  
C. Joaquín Cáceres ◽  
Aarti Jain ◽  
Ginger Geiger ◽  
Jong-Suk Mo ◽  
...  
Keyword(s):  
Genome Rearrangement ◽  
Natural Infection ◽  
The Elderly ◽  
Respiratory Pathogen ◽  
Influenza B Virus ◽  
Influenza B ◽  
B Virus ◽  
Cellular Immune

Influenza B virus (IBV) is considered a major respiratory pathogen responsible for seasonal respiratory disease in humans, particularly severe in children and the elderly. Seasonal influenza vaccination is considered the most efficient strategy to prevent and control IBV infections. Live attenuated influenza virus vaccines (LAIVs) are thought to induce both humoral and cellular immune responses by mimicking a natural infection, but their effectiveness has recently come into question. Thus, the opportunity exists to find alternative approaches to improve overall influenza vaccine effectiveness. Two alternative IBV backbones were developed with rearranged genomes, rearranged M (FluB-RAM) and a rearranged NS (FluB-RANS). Both rearranged viruses showed temperature sensitivity in vitro compared with the WT type B/Bris strain, were genetically stable over multiple passages in embryonated chicken eggs and were attenuated in vivo in mice. In a prime-boost regime in naïve mice, both rearranged viruses induced antibodies against HA with hemagglutination inhibition titers considered of protective value. In addition, antibodies against NA and NP were readily detected with potential protective value. Upon lethal IBV challenge, mice previously vaccinated with either FluB-RAM or FluB-RANS were completely protected against clinical disease and mortality. In conclusion, genome re-arrangement renders efficacious LAIV candidates to protect mice against IBV.

scholarly journals NB protein does not affect influenza B virus replication in vitro and is not required for replication in or transmission between ferrets

2016 ◽  
Vol 97 (3) ◽  
pp. 593-601 ◽  
Author(s):  
Ruth A. Elderfield ◽  
Marios Koutsakos ◽  
Rebecca Frise ◽  
Konrad Bradley ◽  
Jonathan Ashcroft ◽  
...  
Keyword(s):  
Virus Replication ◽  
Influenza B Virus ◽  
Influenza B ◽  
B Virus

scholarly journals A Reverse Genetics Approach for Recovery of Recombinant Influenza B Viruses Entirely from cDNA

2002 ◽  
Vol 76 (22) ◽  
pp. 11744-11747 ◽  
Author(s):  
David Jackson ◽  
Andrew Cadman ◽  
Thomas Zurcher ◽  
Wendy S. Barclay
Keyword(s):  
Amino Acid ◽  
Influenza A ◽  
Amino Acid Change ◽  
Reverse Genetics ◽  
Single Gene ◽  
Neuraminidase Inhibitor ◽  
Influenza B Virus ◽  
Influenza B ◽  
B Virus

ABSTRACT The recovery of recombinant influenza A virus entirely from cDNA was recently described (9, 19). We adapted the technique for engineering influenza B virus and generated a mutant bearing an amino acid change E116G in the viral neuraminidase which was resistant in vitro to the neuraminidase inhibitor zanamivir. The method also facilitates rapid isolation of single-gene reassortants suitable as vaccine seeds and will aid further investigations of unique features of influenza B virus.

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