Peptides binding to bone marrow stromal cell antigen

Details Peptides binding to bone marrow stromal cell antigen Peptides binding to bone marrow stromal cell antigen

1999-04-27

2002-07-02

Nolan, Patrick J. (Department: 1644)

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

C530S412000, C424S184100, C514S014800, C435S004000, C604S005010

Reexamination Certificate

active

06414113

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to peptides binding to bone marrow stromal cell antigen-1 (referred to as “BST-1” hereinafter) and peptides that bind to the antigen BST-1 and inhibit ADP-ribosyl cyclase activity of the antigen. The peptides may be used for treating rheumatoid arthritis (sometimes referred to as “RA” hereinafter), multiple myeloma (sometimes referred to as “MM” hereinafter) and the like.
2. Description of the Related Art
Bone marrow stromal cell lines derived from RA patients were reported to have increased proliferation-enhancing activity on DW34 which is mouse stromal cell-dependent pre-B cell, when compared with those from normal volunteer (J. Immunol., 149, 4088-4095, 1992). It was also reported that bone marrow stromal cell lines from RA and MM patients showed increased proliferation-enhancing activity on pre-B cell, and a novel bone marrow stromal cell antigen-1 was successfully isolated based on the assumption that the bone marrow stromal cells from RA and MM patients must contain some proliferation-accelerator (Proc. Natl. Acad. Sci. USA, 91, 5325-5329, 1994).
BST-1 is a glycosyl-phosphatidylinositol (GPI)-anchored membrane protein carrying hydrophobic signal peptide at the C-terminal. BST-1 is considered to function as a signal transmitter (receptor) since intracellular proteins are phosphorylated or dephosphorylated when BST-1 is stimulated by crosslinking with its polyclonal antibodies (Biochem. Biophys. Res. Commun., 228, 838-845, 1996). BST-1 shows 30% homology with human lymphocyte antigen CD38 at the amino acid level, and it is known that BST-1 has cyclic ADP-ribose hydrolase activity as well as ADP-ribosyl cyclase activity like CD38 (FEBS letters, 356, 244, 1994). As well known, the term “ADP” is an abbreviation for adenosine 5′-diphosphate, and the cyclic ADP-ribose is referred to as cADP-ribose hereinafter.
ADP-ribosyl cyclase activity is an enzymatic action which converts nicotinamide adenine dinucleotide (NAD) to cADP-ribose, and the latter is being watched with interest as a second messenger for releasing Ca
2+
from intra-cellular Ca
2+
stores with a mechanism different from inositol 1,4,5-triphosphate (IP3) (Science, 253, 1143-1146, 1993). Through cADP-ribose hydrolase activity, cADP-ribose is hydrolized to ADP-ribose.
BST-1 and CD38 have their catalytic regions on the extracellular side, and therefore, it would be an interesting theme to investigate how their extracellular enzymatic activities can perform the Ca
2+
release from intracellular Ca
2+
stores, considering that the cADP-ribose can hardly cross the plasma membrane.
It has been shown that arthrosis crevicular fluid of RA patients contains significantly high concentration of soluble BST-1 as compared with that of normal volunteers (Arthritis Rheum., 39, 629-637, 1996), and it is suggested that there may be some relation between ADP-ribosyl cyclase activity of the soluble BST-1 and pathogenesis of rheumatoid arthritis. However, unavailability of an inhibitor specifically inhibiting ADP-ribosyl cyclase activity has hindered researchers from investigating this subject.
SUMMARY OF THE INVENTION
As stated above, precise relationship between BST-1 isolated from stromal cells of RA or MM patients and the pathogenesis has not been established yet. In particular, relation between ADP-ribosyl cyclase activity of BST-1 and the pathogenesis has not been clarified yet. In such a situation, the inventors of the present invention considered that the use of an agent inhibiting such ADP-ribosyl cyclase activity would be effective for elucidating the relation. After extended studies for this purpose, they succeeded in obtaining novel peptides binding to BST-1, and additional novel peptides binding to BST-1 and yet inhibiting ADP-ribosyl cyclase activity thereof. The present invention is based on such findings.
Thus, the invention provides peptides binding to BST-1, in particular, peptides binding to BST-1 and yet inhibiting ADP-ribosyl cyclase activity of BST-1.


REFERENCES:
patent: 94/17184 (1994-08-01), None
Ngo et al. The Protein Folding Problem and Tertiary Structure Prediction, Merz, Editor, Birkhauser Boston pp. 492-495.*
A. Sato et al., “Novel peptide inhibitor of ecto-ADP-ribosyl cyclase of bone marrow stromal cell antigen-1 (BST-1/CD157)”, Biochemical Journal, vol. 337, No. 3, pp. 491-496, Feb. 1, 1999.
M. Torti et al., “Cytoskeleton-dependent inhibition of the ADP-ribosyl cyclase activity of CD38 in thrombin-stimulated platelets”, FEBS Letters, vol. 431, No. 1, pp. 19-22, Jul. 10, 1998.
Y. Kajimoto et al., “Pancreatic islet cells express BST-1, a CD38-like surface molecule having ADP ribosyl cyclase activity”, Biochemical and Biophysical Research Communications, vol. 219, No. 3, pp. 941-946, Feb. 27, 1996.
M. Hara-Yokohama et al., “Ihibition of NAD+glycohydrolase and ADP-ribosyl cyclase activities of leukocyte cell surface antigen CD38 by gangliosides”, The Journal of Biological Chemistry, vol. 271, No. 22, pp. 12951-12955, May 31, 1996.
Y. Okuyama et al., “Human BST-1 expressed on myeloid cells functions as a receptor molecule”, Biochemical and Biophysical Research Communications, vol. 228, No. 3, pp. 838-845, Nov. 21, 1996.

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