Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1993-02-18
1997-11-11
Guzo, David
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 231, C07H 2104
Patent
active
056866011
ABSTRACT:
Dominant negative or trans-dominant mutants of viral proteins represent a new and exciting means of antiviral therapy. However, the extreme specificity of a given dominant negative mutant limits its general utility in treating a broad spectrum of viral diseases, since it can typically interfere with the activity of only a single viral polypeptide encoded by a single virus. A dominant negative mutant of a gene encoding promiscuous viral transactivator protein was isolated in an attempt to generate a polypeptide which could inhibit gene expression and, therefore, virus replication nonspecifically. This mutant, a truncated derivative of the gene encoding herpes simplex virus type 1 (HSV-1) regulatory protein ICP0, was found to behave as a powerful repressor of gene expression from an assortment of HSV-1 and non-HSV-1 promoters in transient expression assays. Unexpectedly, it was also capable of inhibiting the replication of both HSV- 1 and a completely unrelated virus, human immunodeficiency virus, in cell culture. Moreover, a derivative of ICP0 with dominant mutant properties similar to that of pD19T can potentially be created by a failure to splice out the intron 2 sequences; translation of this message results in a derivative of ICP0, called ICPOR, which contains all 241 amino acids encoded by exons 1 and 2 plus an additional 21 amino acids derived from translation into the unspliced second intron. The properties of this dominant negative mutant indicate that it may be successfully utilized in treating a wide variety of different viral infections in vivo.
REFERENCES:
Weber, et al., Journal of Virology, vol. 66, pp. 2261-2267 (1992).
Weber, et al., Journal of General Virology, vol. 73, pp. 2955-2961, (1992).
Perry, et al., J. Gen. Virol., vol. 67, pp. 2365-2380 (1986).
Friedman, et al., Nature, vol. 335, pp. 452-454 (1988).
Guzo David
Monahan Thomas J.
The Penn State Research Foundation
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