Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-04-24
1997-06-03
Wax, Robert A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530350, C07K 1482
Patent
active
056354738
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel use of a biologically active protein, more specifically, to a novel use of protein p53 as an inhibitor of hepatitis B virus replication.
2. Description of the Prior Art
Hepatitis B virus(hereinafter referred to as `HBV`), a causative agent of acute/chronic hepatitis, consists of a partially double-stranded 3.2 kb circular DNA and from which, four proteins are synthesized: they are the core, polymerase, surface antigen and X-gene product(see: Ganem, D. and Varmus, H. E., Annu. Rev. Biochem., 56: 651-693 (1987)).
Four promoters with unique functions have been identified in HBV genome. The pregenomic/core promoter directs the synthesis of 3.6 kb mRNA which contains all the genetic information encoded by the virus. This RNA serves as a replication intermediate and as a template for the synthesis of core and polymerase(see: Seeger, C. et al., Science, 232: 477-484(1986); Yuh, C. H. et al., J. Virol., 66:4073-4084(1992)). The S promoter and the pre-S promoter direct the synthesis of 2.1 and 2.4 kb RNAs utilized for the generation of pre-S1, pre-S2, and S proteins. X promoter directs the transcription of 0.9 kb RNA specific for the synthesis of X gene product. Liver-specific and differentiation state-specific utilization of these promoters are regulated by the two enhancer elements, i.e., enhancer I(ENI) and enhancer II(ENII). These enhancers along with HNF-1(hepatocyte nuclear factor-1) binding element are largely responsible for the restricted tropism of HBV to hepatocytes(see: Antonucci, T. K. and Rutter, W. J., J. Virol., 63:579-583(1989)).
The mechanism of HBV replication differs from that of other DNA viruses in that, like retroviruses, the reverse transcription step is involved. Upon infection of the hepatocytes, a partially double-stranded genome is converted to a complete double-stranded circular, supercoiled DNA. Employing this as a template, 3.6 kb RNA, which is called the pregenome, is transcribed. The pregenome is packaged into a nucleocapsid and is reverse-transcribed using polymerase as an initiation primer(see: Wang, G. H. and Seeger, C., Cell, 71:663-670(1992); Wang, G. H. and Seeger, C., J. Virol., 67:6507-6512(1993)) to generate the minus-strand, single-stranded DNA. The polymerization of the second strand follows until approximately half of the genome is synthesized, resulting in the generation of partially double-stranded circular genome, which is coated and secreted by the infected cells(see: Tiollais, P. et al., Nature, 317:489-495(1985); Ganem, D. and Varmus, H. E., Annu. Rev. Biochem., 56:651-693(1987)).
Despite extensive epidemiological evidences that chronic carriers of HBV have an increased risk of developing hepatocellular carcinoma(hereinafter referred to as `HCC`) (see: Beasley, R. P. et al., Lancet ii, 1129-1133(1981)), the exact mechanism by which HBV cause HCC still remains unclear. Although integration of HBV DNA into the host chromosome is observed in cancer patients, integration appears to occur at random sites rendering it unlikely that integration-mediated alteration of adjacent gene expression is the cause of HCC(See: Chen, D. S., Nature, 262:369-370 (1993)).
On the other hand, p53, a 53 kDa protein ubiquitous in mammalian cell, was reported to have the function of tumor suppressors. It was first isolated as a coprecipitated form with SV40 large tumor antigen(see: Lane, D. P. and Crawford, L. V., Nature, 278:261-263(1979); Linzer, D. I. H. and Levine, A. J., Cell, 7:43-52(1979)), and its biological function and biochemical properties have been further investigated with the aid of molecular biology, e.g., cDNA cloning of p53 in various organisms. It has been also reported that mutation in p53 tumor suppressor gene is the most frequently occurring event in a wide variety of human tumors(see: Hollstein, M. et al., Science, 253:49-53(1991)). However, the precise mechanism how p53 exerts its tumor suppressing function is not yet clear, except for recent reports suggesting that at leas
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K. Yaginuma et al., Hepatitis B Virus(HBV)
Lee Hyun-Sook
Moon Hong-Mo
Yun Yung-Dae
Carlson K. Cochrane
Mogam Biotechnology Research Institute
Wax Robert A.
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