Basic peptides and pharmaceutical compositions containing same

Details Basic peptides and pharmaceutical compositions containing same Basic peptides and pharmaceutical compositions containing same

2001-02-23

2003-08-05

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C424S001690, C424S009100, C424S009341, C424S009600, C514S002600, C514S013800, C514S014800, C514S015800, C514S016700, C530S300000, C530S324000, C530S326000, C530S327000, C530S328000, C530S329000

Reexamination Certificate

active

06602852

ABSTRACT:

The present invention relates to novel compounds and pharmaceutical preparations comprising same, their use in the treatment of and in the diagnosis of certain diseases, in particular of diseases involving changes of cell membrane lipid asymmetry
(CMLA) is the phenomenon, by which normal eukaryotic cells have an asymmetrical organization of the phospholipids comprising their plasma membranes; the outer membrane leaflet is formed predominantly with the cholinephospholipids: (phosphatidylcholine [PC] and sphingomyelin), whereas the majority of the amino phospholipids (phosphatidylserine [PS] and phosphoethanolamine [PE]) are confined to the membrane's inner leaflet (Zwaal R F A & Schronit A J, Blood 1997;89:1121-1132) The physiolocical importance of CMLA is exemplified by the fact that its maintenance requires a continuous, considerable investment of energy by the cell (Seigneuret M & Devaux P F, Proc. Natl. Acd. Sci., 1984;81:3751) At least three distinct systems are active in the regulation of CMLA:
1. Aminophospholipid translocase (APT): an ATP-dependent enzyme which transports PS and PE from the outer to the inner membrane leaflet, against the concentration gradient (Daleke D L & Huestis W H, Biochemistry 1985;24:5406).
2. ATP-dependent floppase: transports amino-phospholipids and cholinephospholipids from the inner to the outer leaflet. This enzyme is tenfold slower than APT (Andrick C et al., Biochim. Biophys. Acta 1991;1064:235).
3. Lipid scramblase: A potent, Ca
2+
-dependent and ATP-independent enzyme, that rapidly moves phospholipids back and forth between the two membrane leaflets (flip-f-lo), leading within minutes to loss of CMLA (Zwaal R F A & Schronit A J, Blood 1997;29:1121-1132)
In addition, other factors, such as membrane anchoring of cytoskeletal proteins have been suggested to assist in CMLA maintenance.
Whereas the maintenance of CMLA is fundamental to normal cell physiology, its loss, with subsequent surface exposure of PS plays a role in numerous states of both physiological and pathological characters. The surface exposure of anionic phospholipids plays an indispensable role in the formation of a catalytic surface for the assembly of several clotting factor complexes. Thus, the loss of CMLA in activated platelets as well as in other cell types (e.g. endothelial cells), is an important factor in normal blood coagulation. However, CMLA loss also assists in the initiation and/or propagation of abnormal, excessive blood clotting in numerous disorders. These disorders include, among others:
1. Arterial or venous thrombosis (Thiagarajan P & Benedict C R, Circulation 1997;96:2339-2347; Van Ryn McKenna J, et al., Throm. Hemost. 1993;69:227-230).
2. Sickle cell disease (Tait J F & Gibson D, J. Lab. Clin. Med. 1994;123:741).
3. Beta-thalassemia (Borenstein-Ben-Yashar Y, et al., Am. J. Hematol. 1994;47:295; Ruf A, et al., Br. J. Haematol. 1997;98:51-56).
4. Antiphospholipid antibody syndrome; among others in systemic lupus erythematosus. Lack of CMLA has been specifically linked to the recurrent abortions associated with said syndrome (Rand J H, et al., N. Engl. J. Med. 1997;337:154-160).
5. Shed membrane microparticles, e.g., during cardiopulmonary bypass, (Nieuwland R et al., Circulation 1997;96:3534-3541; Aupeix K, et al., J. Clin. invest. 1997; 99:1546-155).
Apoptosis is another major situation in which CMLA loss takes place. Apoptosis is an intrinsic program of cell self-destruction or “suicide”, which is inherent in every eukaryotic cell. In response to a triggering stimulus, cells undergo a highly characteristic cascade of events of cell shrinkage, blebbing of cell membranes, chromatin condensation and fragmentation, culminating in cell conversion to clusters or membrane-bound particles (apoptotic bodies), which are thereafter engulfed by macrophages (Boobis A R, et al., Trends Pharmacol. Sci. 10:275-280, 1989; Bursch W, et al., Trends Pharmacol. Sci. 13:245-251, 1992). Loss of CMLA is quite a universal phenomenon in apoptosis (Van den Eljnde S M, et al., Cell death Diff. 1997;4:311-316). Loss of CMLA occurs early in the apoptotic cascade, immediately following the point of cell commitment of the death process (Van-Engeland M, et al., Cytometry 1998;31:1-9; Martin S J, et al., J. Exp. Med. 1995;182:1545-1556). It has also been shown that the loss of CMLA is an important factor in the recognition and removal of apoptotic cells by macrophages (Balasubramanian K, et al., J. Biol. Chem. 1997;272:31113-31117). A strong correlation has recently been drawn between the loss of CMLA and the potent pro-coagulant activity of apoptotic cells (Bombeli T, et al., Blood 1997; 89:2429-2442; Flynn P D, et al., Blood 1997;89:4378-4384) The latter activity in apoptotic endothelial cells, such as those recently recognized in atherosclerotic plaques (Kockx M M, et al., Circulation 1998;97:2307-2315, Mallat Z, et al., Circulation 1997;96:424-428), probably plays an important role in the pathogenesis of thrombotic vascular disorders.
The diagnosis of the loss of CMLA may therefore serve as an important tool for the detection of cell death, specifically by apoptosis. A method for the detection of cell death may have many applications, both as a diagnostic tool and as a method to monitor the disease course in numerous disorders associated with impairment of tissue homeostasis. Among these applications are:
1. Monitoring of a response to anti-cancer therapy:
Currently there is a lag period between the time of administration of anticancer drugs and the time of evaluation or their efficacy. Thus, in case of failure of a therapeutic regimen, this lag time may be hazardous to the patient in two aspects:
a. loss of precious time without an effective therapy; and
b. unnecessary exposure of the patient to drug adverse effects.
Therefore, there is clearly a need for an early detection of tumor response to treatment. Since anti-tumor drugs exert their effects by induction of apoptosis (Eastman A, Cancer Cells, 1990;2:275-280), the detection of apoptosis, potentially by detection of CMLA loss may be useful for monitoring tumor response.
2. Diagnosis of disorders of inappropriate excessive apoptosis. These disorders include, among others, AIDS, neurodegenerative disorders, myelodysplastic syndromes and various ischemic or toxic insults (Thompson C B, Science 1995;267:1456-1461).
3. Monitoring of graft survival following organ transplantation. The increasing use of organ transplantation for the treatment of end-stage organ failure emphasizes the need for the development of methods for sensitive monitoring of graft survival. Apoptosis plays a major role in graft cell loss (Matsuno T, et al. Transplant Proc. 1996;28;1226-1227; Dong C et al., Lab. Invest. 1996;74:921-931).
4. Monitoring of response to cytoprotective treatments. The current intensive research of cytoprotective agents, towards development of drugs capable or inhibiting cell loss in various diseases (Thompson C B, Science 1995;267:1456-1461), dictates a need for measures to evaluate the effects of such compounds, i.e., monitoring of cell death, in all levels of research, from in vitro tissue culture studies, through in vivo animal models to human clinical studies.
5. Basic research of apoptosis in tissue cultures and animal models.
The loss of the normal CMLA has, as indicated above, wide implications for various pathophysiological states. A compound capable of selectively binding to membranes upon CMLA loss, thus serving as a marker for this phenomenon, may therefore have wide diagnostic applications. Moreover, by shielding the exposed anionic phospholipids, specifically PS, such compound may be a useful therapeutic agent, for example for the above-mentioned disorders, which are associated with excessive pro-coagulant activity caused by the membrane phospholipid re-organization.
In addition, a compound capable of detecting cells undergoing apotosis may have important applications for targeting drugs to apotosis-inflicted tissues. Apoptosis and its major control systems are shared by all tissues

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