Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
1996-09-13
2002-09-24
Scheiner, Laurie (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
C435S007100, C436S501000, C436S506000, C436S507000
Reexamination Certificate
active
06455244
ABSTRACT:
The present invention relates to retro peptides, as well as antibodies thereto, and to their uses, chiefly in the field of preparation of pharmaceutical compositions, in particular vaccines, and for in vitro diagnosis of various pathologies.
The development of neuropeptides, peptide hormones and antibiotics based on peptides or of synthetic vaccines based on peptides faces great problems due to the high sensitivity of peptides to proteolysis, which limits, inter alia, oral and parenteral administration.
For several years, attention has been paid to the synthesis of peptide analogues in order to investigate peptides which mimic natural peptides or proteins and have an increased activity and longer biological half-life compared to the latter. For example, peptide analogues have been obtained by replacing the L amino acids of the natural peptide by the corresponding D amino acids, or by non-natural residues (for example sarcosine and &bgr;-alanine), or also by modification of peptide bonds of the natural peptide (Chorev, M. & Goodman, M. (1993), Acc. Chem. Res. 26, 266-273; Marraud et al., (1993), Biopolymers, 33, 1135-1148).
These modifications give pseudopeptides or peptides which mimic the natural peptides or proteins (also called peptidomimetics) and have a metabolic stability which is greater than that of the latter, since the majority of natural proteases cannot cleave the D amino acids and non-peptide bonds.
The major problem encountered with such pseudopeptides is that of preserving their biological activity with respect to that of the natural peptide, or of the natural protein which they are supposed to mimic.
The D form of the protease HIV-1 has recently been synthesized (De L. Milton et al., (1992), Science, 256, 1445-1448). As was to be expected, the enantiomeric protein showed a reciprocal chiral specificity such that the enzyme was incapable of cleaving the normal L substrate, but hydrolysed its D enantiomer.
In contrast, Wen and Laursen (Wen, D. & Laursen, R. A., (1993), FEBS Lett., 317, 31-34) have shown that both the D and the L form of an &agr;-helicoidal anti-icing polypeptide bond equally well to the same substrate of achiral ice, while Wade et al. (Wade et al., (1990), Proc. Natl. Acad. Sci., USA, 87, 4761-4765) found that the L and D enantiomers of several antibiotics which form channels were all as active as one another.
The modified peptides could be used as potential synthetic vaccines if they could induce the formation of antibodies which recognize the non-modified antigenic structures of the corresponding pathogen and neutralize its infectious character.
However, in comparison with the considerable work carried out to date in the field of production of antibodies to natural proteins or to synthetic peptides derived from the latter, and the study of cross-reactions between such antibodies and these natural proteins or peptides, little is known of the immune response to peptide analogues, in particular to the D peptides and the peptides containing modified bonds.
Several authors have asserted that pseudopeptides probably have very little or no immunogenicity, since they could not be transformed and presented to molecules of major histocompatibility complex (MHC) in order to be recognized by auxiliary T cells or by cytotoxic T lymphocytes. Consequently, Dintzis et al. (8) have recently reported that the L enantiomer of rubrexodin induces a strong immune response by producing immunoglobulins of the G isotype (IgG), while the corresponding protein made up of amino acids all with the D configuration does not induce an immune response.
The object of the present invention is to provide pharmaceutical compositions, and more particularly vaccines, comprising peptide analogues which have a half-life which is clearly superior to that of natural proteins or that of synthetic peptides which are or are not derived from these natural proteins (these natural proteins, or peptides which are or are not derived from the latter, also being referred to in the following by the expression “parent proteins or peptides”), of which they are the analogues, while having a comparable, or even higher, biological, and more particularly immunological, activity to that of the abovementioned parent proteins or peptides.
The object of the present invention is also to provide methods for in vitro diagnosis of diseases associated with the presence in the organism of an individual of endogenous or exogenous proteins, these methods being carried out with the aid of peptide analogues as defined above and having the advantage of being more efficient than the current methods of diagnosis carried out with the aid of the parent peptides or proteins. The object of the present invention is thus, in particular, to provide new kits for implementing such methods of diagnosis.
The present invention chiefly relates to the use
of compounds of the peptide type (also called peptide analogues, or pseudopeptides, or peptidomimetics),
in which at least one of the —CO—NH— bonds, and advantageously all the —CO—NH— bonds, of the peptide chain of the corresponding parent peptide (containing no —NH—CO— bond in its peptide chain) is (are) replaced by (a) —NH—CO— bond(s),
the chirality of each aminoacyl residue, whether involved or not in one or more of the abovementioned —NH—CO— bonds, being either maintained or reversed with respect to the corresponding aminoacyl residues which make up the said parent peptide,
these compounds of the peptide type also being called immunoretroids, or
antibodies to the said immunoretroids (anti-immunoretroid antibodies),
the said immunoretroids being capable of forming a complex with the said anti-immunoretroid antibodies as well as with antibodies to the parent peptides or proteins (called anti-parent antibodies), and/or to the enantiomers of these parent peptides or proteins,
for the preparation:
of a medicament intended for prevention or treatment of diseases associated with the presence in the organism of an individual of an exogenous or endogenous protein capable of being recognized by the abovementioned anti-immunoretroid or anti-parent antibodies, or
of a medicament intended for prevention or treatment of diseases involving molecules of major histocompatibility complex and/or T cell receptors,
of a medicament intended for prevention or treatment of diseases associated with the presence in the organism of an individual of an antibody to an endogenous or exogenous protein capable of being recognized by a said immunoretroid,
or for implementation of a method of in vitro diagnosis of the abovementioned diseases.
As has already been seen above, the abovementioned term “parent peptide” is to be understood as meaning
a peptide which exists as such in the natural state, in particular in a microorganism or in a higher organism (in particular in the human organism),
or any peptide of immunological interest obtained by peptide synthesis,
or a peptide derived from a protein such as exists in the natural state in the abovementioned organisms, in particular by fragmentation of the said protein (in particular with the aid of suitable proteases, followed by purification of the peptide in question), or by peptide synthesis (by the methods conventionally used in this field)
or a peptide derived from a protein such as exists in the natural state but of which the immunological activity has been modified, maintained or optimized by replacing certain amino acids of the natural sequence, for example following screening of a library of analogous peptides obtained by peptide synthesis.
It goes without saying that the —CO—NH— and —NH—CO— bonds should be considered in the above and the following, in the direction of the parent peptide chain from the amino-terminal (N-terminal) end towards the carboxy-terminal (C-terminal) end.
The immunoretroids used in the invention can be linear or cyclic or branched.
The immunoretroids used in the context of the present invention are compounds made up of a peptide chain in which at least one of the residues, this residue being, as appropriate, of opposite chirality t
Briand Jean-Paul
Guichard Gilles
Muller Sylviane
Van Regenmortel Marc
Biomerieux S.A.
Nixon & Vanderhye PC
Parkin Jeffrey S.
Scheiner Laurie
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