Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 11 to 14 amino acid residues in defined sequence
Patent
1992-01-17
1993-09-14
Hill, Jr., Robert J.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
11 to 14 amino acid residues in defined sequence
435 691, 530826, 5303894, 930224, C07K 700
Patent
active
052450104
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a polypeptide which inhibits the replication of Herpes Simplex Virus (HSV) and like viruses and its therapeutic use against infections of such viruses.
2. Description of the Prior Art
HSV exists as several serotypes of which HSV-1 is one which is clinically significant in relation to cold sores. HSV-1 is a DNA virus which is transcribed and replicated within the cell nucleus. As with many other viruses, the genes are transcribed into mRNA at different times. Certain important genes which are the first to be transcribed are denoted immediate-early (IE) or ".alpha.". Their transcription is enabled by promoter sequences which lies to the 5' end or upstream of the ATG start codon of the gene. Further upstream from the promoter the IE genes have a distinctive nucleotide sequence which is a consensus (common) sequence TAATGARAT (where R=purine, i.e. can be G or A).
The IE genes of HSV are induced by a component of the virion, first identified by M. E. M. Campbell, J. W. Palfreyman and C. M. Preston, Journal of Molecular Biology 180, 1-19 (1984), as "Vmw 65". Vmw 65, which has also been referred to as VP16, is a tegument protein which lies between the viral membrane and the capsid. Vmw 65 is said to be "trans-acting" or "transactivating". This language indicates merely that it is some soluble factor which acts on the viral DNA to regulate it. Yet another name for Vmw 65 is the .alpha.-Trans Inducing Factor or .alpha.-TIF, meaning that it acts on the viral DNA to induce transcription of the IE (.alpha.) genes.
M. E. M. Campbell et al., loc. cit. speculated that Vmw 65 might bind to the DNA in the TAATGARAT region, either directly or indirectly by modifying a host cell polypeptide. Later work, beginning with that of T. M. Kristie and B. Roizman, Proc. Natl. Acad. Sci. USA, 84, 71-75 (1987), has shown that the TAATGARAT region, which is termed a "cis-acting site" or the .alpha.-Trans Induction Cis-acting (.alpha.-TIC) site, does not bind directly to Vmw 65, but does bind to one or more host cell proteins. Various groups of workers have identified host cell proteins which bind both to the TAATGARAT region and to Vmw 65. They have been variously designated as ".alpha.-H1", "HC3", "octamer-binding protein", "OTF-1" and "TAATGARAT Recognition Factor" (TRF), all of which are probably identical. The TRF nomenclature is used in this specification.
Current knowledge is summarised by C. I. Ace et al., J. Virology 63, 2260-2269 (May 1989). Vmw 65 indicates the induction of IE genes by associating with cellular proteins, to form a complex known as IEC or TRF.C, which is able to bind specifically to DNA sequences which include TAATGARAT. In other words, IE gene induction involves a complex which is at least ternary between, at least, Vmw 65, TRF and a TAATGARAT region sequence.
It would be desirable to block the formation of this complex and thereby block induction of IE gene transcription of HSV. C. I. Ace et al., supra, have demonstrated that a virus mutant which lacks the ability to form such a complex with Vmw 65 and TRF replicates very poorly at low multiplicity of infection (MOI). Low MOI would be encountered clinically. Attempts have therefore been made to identify regions of Vmw 65 responsible for complex formation. It might then be possible to synthesise a short polypeptide which would compete with Vmw 65 in the formation of the complex.
S. J. Triezenberg, R. C. Kingsbury and S. L. McKnight, Genes & Development 2, 718-729 (1988) explored Vmw 65 structure/function with an assay for IE gene transcriptional induction and for the ability of Vmw 65 deletion mutants to inhibit IE transciptional induction by normal Vmw 65. They showed that if the carboxy terminus of Vmw 65 was deleted, the protein would no longer induce IE transcription, but reported that this deleted protein could prevent IE induction by normal Vmw 65. Using various deleted forms of Vmw 65 they showed that the boundaries for this inhibitory activity (i.e. inhibition of normal Vm
REFERENCES:
G. Werstuck & J. P. Capone "Mutational Analysis of Herpes Simplex Virus . . . Vms 65" Gene 75:213-224, 1989.
S. Triezenberg et al. "Functional Dissection of VP16 . . . " Genes & Development 2:718-729 1988.
R. Greaves et al., J. Virology 63(4) 1641-1650 Apr. 1989.
B. M. Datia et al. Nature 321:439-441 May 22, 1986.
Pellett et al., "Nucleotide sequence and predicted . . . " Proc. Natl. Acad. Sci. USA, vol. 82, 1985, pp. 5870-5874.
Greaves Richard F.
O'Hare Peter F. J.
Hill Jr. Robert J.
National Research Development Corporation
Spector L.
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