Therapeutic compounds

Details Therapeutic compounds Therapeutic compounds

1996-03-06

1999-10-05

Achutamurthy, Ponnathapura

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

15 to 23 amino acid residues in defined sequence

4241481, 4241601, 435 71, A61K 3800, A61K 3942, G01N 3353

Patent

active

059626356

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a biologically-active peptide fragment of the Nef protein of human immunodeficiency virus, to pharmaceutical compositions comprising these peptides or biologically-active analogues thereof, to antagonists of the peptides and to pharmaceutical compositions comprising these antagonists, and to therapeutic and screening methods utilising compounds and compositions of the invention.


BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV-1), the aetiological agent of AIDS, is distinguished by a genomic structure which is more complex than observed with other animal retroviruses The gemome of HIV-1 has been found to encode the major structural proteins, derived from the gag, pol and env gemes, and at least seven mon-essential auxiliary proteins derived from the tat, rev, nef, vif, vpu, vpr and tev genes (1,2). Several of these proteins have clearly defined functions; for example, it is kown that Tat and Rev regulate viral gene expression, while Vif and Vpu are thought to be required for virion morphogenesis and maturation (3,4,5). However, the function of the other auxiliary proteins such as Nef is more ambiguous.
The nef gene product, a 25-30 kDa protein, is modified by N-terminal myristoylation and phosphorylation and is expressed early in infection (6,7). It is associated with cytoplasmic membrane structures in HIV-infected cells. The Nef protein is encoded by a single open reading frame of the virus genome overlapping with the 3' long terminal repeat sequence (LTR; 8,9). While recent studies of Rhesus monkeys infected with simian immunodeficiency virus have suggested an important role for Nef in the maintenance of high virus load and in viral pathogenesis (10), and while prolonged survival in HIV-infected patients is correlated with the absence of Nef, the biological function and mechanism of action of Nef remain controversial. Nef has been reported to be a negative regulator of HIV-1 replication (2,10,11): T cells stably transformed for Nef expression demonstrate a delay in virus multiplication (11). Further reports have suggested that Nef may act to repress transcription from the HIV-1 LTR (12,13,14) such that Nef may act to regulate the positive effects of the viral transactivator, Tat. However, other studies have been saei to confirm the inhibitory effects of Net on viral tr scription or replication in vitro, and indeed in one instance showed that Nef enhances viral replication (15).
We have found that Nef possesses no G-protein activities, using highly purified recombinant Nef protein produced in either E. coli or yeast.
The affect of HIV-1 Nef on host-cell function is equally controversial. The major targets for HIV-1 infection are CD4.sup.+ T-lymphocytes (16,17). This cell population, most of which constitutes the T-helper cell category, is intimately involved in the host cell response to infection. Specific interactions of the CD4 antigen with invariant determiants of MHC class II molecules on antigen-presenting cells, in conjunction with recognition of peptide antigen by the T-cell receptor (TCR), initiate the events which lead to the expression of the activated T-cell phenotype. Moreover, it has been proposed that CD4 and its associated tyrosine kiase may play am active role in the CD3/TCR activation process (18,19). By use of a vaccinia virus recombinant expressing the nef gene, or the nef gene under control of a murine retrovirus LTR, it has been found that the protein is capable of down-regulating CD4 cell surface expression in CEM T4 cells (20,21). Down-regulation occurred after translation of CD4 mRNA and before expression of mature protein on the cell surface. Furthermore, there is evidence that virally-encoded Nef protein interferes with a signal emanating from the TCR complex that induces IL-2 gene transcription (22). Hence, rather than affecting viral replication, Nef may act to alter the normal host cell response to infaction by impairing signal transduction pathways. However, interpretation of these results requires caution because of findings that cel

REFERENCES:
patent: 5221610 (1993-06-01), Montagnier et al.
Choppin et al., HLA-Binding Regions of HIV-1 Proteins: I. Detection of Se HLA Binding Regions in the HIV-1 Nef Protein, J. Immunol. 147, 569-574, see Abstract, Jul. 1991.
Delassus, Sylvie, Cheynier, Remi and Wain-Hobson, Simon, Evolution of Human Immunodeficiency Virus Type I, vol. 65, No. 1, 1991 pp. 225-231.
Ahmad, Nafees, Venkatesan, Sundarorajan, Nef Protein of HIV-1 Is a Transcriptional Repressor, Science, vol. 241, pp. 1481-1485.
Fischer, Amanda Infectious Mutants of HTLV-III with Changes in the 3' Region and Markedly Reduced, Science vol. 233, pp. 655-659.
Luciw, Paul A., Mutational analysis of the human immunodficiency virus, Proc. Natl. Acad. Sci. USA, vol. 84, pp. 1434-1438.
Luria, Sylvie, Expression of the Type 1 human immunodeficiency virus Nef protein, Proc. Natl. Acad. Sci. vol. 88, pp. 5326-5330.
Nature, vol. 330, Nov. 19, 1987, pp.266-269, B. Guy et al, "HIV F/3' orf encodes a phosphorylated GTP-binding protein resembling . . . ".
International Journal of Peptide And Protein Research, vol. 35, No. 1, Jan. 1990, pp. 63-72, Sabatier et al, "Large Fragments of nef-protein and gp110 envelope glycoprotein from HIV-1".
AIDS, vol. 6, No. 8, Aug. 1992, pp. 787-791, L. Poulin et al, "The HIV-1 nef gene product is associated with phophorylation . . . ".
Journal of Virology, vol. 66, No. 9, Sep. 1992, pp. 5256-5264, Blumberg et al, "Human Immunodeficiency Virus type 1 nef . . . ".

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