Cyclic analogs of tuftsin

Details Cyclic analogs of tuftsin Cyclic analogs of tuftsin

1992-07-22

2001-01-23

MacMillan, Keith D. (Department: 1618)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C530S317000

Reexamination Certificate

active

06177405

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to peptides with useful biological activity, and more specifically, to analogs of the peptide tuftsin, Thr-Lys-Pro-Arg (TKPR).
A variety of factors are involved in vivo in the modulation of the immunological system, and also in the growth and differentiation of normal and tumor cells. Tuftsin is one such factor. Tuftsin, which is located between residues 289 and 292 of the heavy chain of leukokinin (a leukophilic IgG), has been found to have a number of interesting biological activities, such as antitumor, anti-infection, anti-AIDS, and growth factor activities, and enhancement of the phagocytic and cytotoxic activities of leukocytes.
Without wishing to be bound to any particular theory of activity, it is presently believed that tuftsin is released through a process in which the carboxyl-terminus of tuftsin in the Fc portion of the leukophilic IgG is cleaved from the adjacent part of the molecule by a splenic enzyme, tuftsin endocarboxypeptidase. Tuftsin with the exposed carboxyl terminus is then transported as an integral part of the leukophilic IgG to target cells, polymorphonuclear leukocytes (PMNs). The leukokinin molecule binds to the Fc receptor on the membrane of the PMN. There tuftsin is cleaved at the NH
2
-terminus from the Fc portion of the heavy chain of the leukokinin by a specific trypsin-like protease (leukokininase) on the membrane of the target cells. Tuftsin thus released binds to a specific PMN membrane receptor resulting in stimulation of phagocytosis. Tuftsin is now also known to bind monocyte-macrophages and natural killer (NK) cells and modulate their cellular functions.
The physiological importance of tuftsin has been demonstrated in patients with congenital familial tuftsin abnormality; many such individuals produce a peptide which competes with tuftsin, and are more susceptible to infection than are normal subjects. Similar susceptibility to infection can be observed in splenectomized hosts, presumably due to loss of the spleen enzyme, tuftsin endocarboxypeptidase. Tuftsin deficiency has also been found among patients with sickle cell disease, AIDS, AIDS-related complex, acute granulocytic leukemia, myelofibrosis, and idiopathic thrombocytopenic purpura, all of whom also exhibit increased susceptibility to infection.
Researchers have attempted to find analogs of tuftsin which possess improved activity in one or more respects. However, most of the analogs synthesized either have not possessed the desired activity, or have been found to be competitive inhibitors of tuftsin. Therefore, a need exists for peptides which have advantages in biological activity or in other respects over tuftsin.
SUMMARY OF THE INVENTION
The present invention relates to a biologically active peptide selected from the group consisting of cyclo[Thr-Lys-Pro-Arg-Gly] (SEQ ID no. 1)and pharmaceutically acceptable salts thereof, and cyclo[Thr-Lys-Pro-Arg-Asp] (SEQ ID no. 2) and pharmaceutically acceptable salts thereof. The present invention also relates to a therapeutic composition which comprises a pharmaceutically acceptable carrier and at least one of the above peptides.
The above cyclic tuftsin analogs are believed, based on studies performed using high temperature quenched molecular dynamics modeling, to adopt aspects of the conformational distribution in solution similar to that of linear tuftsin. This and the advantage of cyclization are believed to aid in the binding of these analogs to tuftsin-specific receptor sites, and thus to result in biological activity similar to that of tuftsin.
The peptides of the present invention should be useful as immunoaugmenting agents with growth factor activity, including use for prophylaxis and treatment of cancer and infections such as AIDS, infections related to sickle-cell disease, splenectomy, ambulatory peritoneal dialysis, therapy-induced immune suppression, lupus erythematosus, trauma, and idiopathic thrombocytopenic purpura, and tuftsin abnormality disease.
The peptides of the present invention have the particular advantage of greater potency than tuftsin itself. In addition, they retain useful activity when administered orally, due to their resistance to enzymatic degradation.


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