Concentrations of the synthetic polymer polyriboinosinic.polyribocytidylic acid that produced no detectable toxicity in normal L cells produced marked cytotoxicity in L cells treated with interferon. This increase in the susceptibility of cells to the toxicity of the polymer was also observed in human cells and secondary mouse embryo cells treated with homologous interferons before exposure to the polynucleotides. The degree of enhancement of toxicity was dependent on the concentration of interferon to which the cells were exposed. The ratio of antiviral activity induced by interferon to enhancement of toxicity by interferon remained constant through about 1000-fold purification. Various interferon preparations induced by viruses or by polyriboinosinic.polyribocytidylic acid in vivo or in vitro, and international reference standard interferons all exhibited enhancement of toxicity. Both enhancement of toxicity and antiviral activity were destroyed by trypsin and by incubation at 56 degrees for 1 hr, did not act on heterologous cells, were not sedimented by ultracentrifugation, and were not inactivated by ribonuclease, deoxyribonuclease, irradiation with ultraviolet light, or exposure to a pH of 2.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
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This short review article on some pertinent observations in the unfolding story of interferon is dedicated to Professor Ilona Béládi on the occasion of her 80th birthday. This by no means covers the whole story on interferon. It just highlights some of the more striking findings made with interferon (or its inducers) over a time span of almost 50 years since its original discovery (in 1957) by Isaacs and Lindenmann. These observations concern (i) the induction of interferon by synthetic polyanions such as polyacrylic acid and polymethacrylic acid; (ii) the prolonged antiviral activity shown by polyacrylic acid in vivo; (iii) the interferon-inducing ability of double-stranded RNAs such as poly(I) x poly(C) and (iv) mismatched derivatives thereof (i.e. ampligen); (v) the cloning and expression of interferon-beta, and (vi) its usefulness in the treatment of multiple sclerosis; (vii) the potential of (pegylated) interferon-alpha in the treatment of hepatitis C and (viii) the therapy/prophylaxis of SARS; (ix) the efficacy of interferon (inducers) in the experimental treatment of flavivirus encephalitis and enterovirus myocarditis; and, finally, (x) the role of interferon in the activity shown by S-adenosylhomocysteine inhibitors such as 3-deazaneplanocin A against experimental Ebola virus infections in mice.
The murine mammary FM3A/O and the thymidylate (dTMP) synthetase-deficient FM3A/TS- carcinoma cell lines can be considered as a novel and useful test system for the detection of nucleoside analogues which are directly aimed at the thymidylate synthetase. These compounds should be inhibitory for FM3A/O but not for FM3A/TS- cells, and their inhibitory effects on FM3A/O cell growth should be readily reversed by exogenous dThd within the concentration range of 5-20 microM.
A rapid and convenient method has been developed to monitor the inhibition of inosinate (IMP) dehydrogenase by antimetabolites in intact human CEM lymphocytes. This method is based on the determination of 3H release from [2,8-3H]hypoxanthine ([2,8-3H]Hx) or [2,8-3H]inosine ([2,8-3H]Ino). The validity of this procedure was assessed by evaluating IMP dehydrogenase inhibition in intact CEM cells by the well-known IMP dehydrogenase inhibitors ribavirin, mycophenolic acid and tiazofurin. As reference materials, several compounds that are targeted at other enzymes in de novo purine nucleotide anabolism (i.e. hadacidine, acivicin) or catabolism (i.e. 8-aminoguanosine, allopurinol) were evaluated. There was a strong correlation between the inhibitory effects of the IMP dehydrogenase inhibitors (ribavirin, mycophenolic acid, tiazofurin) on 3H release from [2,8-3H]Hx and [2,8-3H]Ino in intact CEM cells and their ability to decrease intracellular GTP pool levels. The other compounds (hadacidine, acivicin, 8-aminoguanosine, allopurinol) had no marked effect on 3H release from [2,8-3H]Hx. Using this method, we demonstrated that the novel ribavirin analogue, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide, is a potent inhibitor of IMP dehydrogenase in intact cells.
Pyridine N-oxide derivatives represent a new class of anti-HIV compounds, for which some members exclusively act through inhibition of HIV-1 reverse transcriptase and thus characteristically behave as non-nucleoside reverse transcriptase inhibitors. Other members act, additionally or alternatively, at a post-integrational event in the replication cycle of HIV, that is, at the level of HIV gene expression. Repeated administration of one of the prototype compounds (JPL-32) to DBA/2 and hu-PBMC-SCID mice demonstrated, in the absence of any acute toxicity, protective activity against HIV-induced destruction of CD4 human T lymphocytes.
