Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Reexamination Certificate
2001-08-03
2004-09-14
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
C530S327000, C514S011400, C514S015800
Reexamination Certificate
active
06790935
ABSTRACT:
This application is the U.S. national phase of international application PCT/IB00/00133 filed Feb. 7, 2000, which designates the U.S., the entire content of which is incorporated herein by reference.
The present invention relates to cyclosporin derivatives in which the peptide sequence comprises at least one non-natural amino acid of the pseudo-proline type. It also relates to a method of preparing the said derivatives.
Cyclosporins constitute a family of secondary metabolites obtained by fermentation. These substances possess remarkable biological properties, including immuno-suppression, and the ability to induce nerve proliferation in neurodegenerative diseases or to stop replication of the HIV-1 virus. About thirty cyclosporins have so far been isolated from natural sources. The best known, on account of its use in organ transplantation, is Cyclosporin A (CsA). It was subsequently found that the same Cyclosporin A might open up new pathways in the treatment of AIDS by inhibiting activation of the CD4
+
cells.
Cyclosporins consist of a complex cyclic peptide sequence of eleven amino acids, some of these being non-natural amino acids that are frequently methylated on the nitrogen atom. These substances are strongly hydrophobic in character, which complicates their administration in a physiological medium.
At present, there is still a need to modify the structure in order to improve the biological activity and/or physicochemical properties of the existing cyclosporins, whether natural or synthetic.
One of the aims of the present invention, therefore, is to make available cyclosporin derivatives of natural or synthetic origin, in which the pharmacological specificity has been improved, preferably to favor inhibition of CD4
+
cell activation so as to stop replication of the HIV-1 virus.
Another aim of the present invention is to make available cyclosporin derivatives, of natural or synthetic origin, of which the physical properties have been modified so as to confer on them a certain hydrophilic character, in order to increase their solubility in a physiological medium and so to facilitate their administration.
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Traber et al,The Journal of Antibiotics, 1989, 42, 591-7 “Cyclosporins -New Analogues by Precursor Directed Biosynthesis.”.
Fisher et al,Biomed. Biochem. Acta, 1984, 43, 1101-11 “Detection of enzyme catalysis for cis-trans-isomerisation of peptide bonds using proine-containing peptides as substracts.”.
Wöhr et al.,J. Am. Chem. Soc., 1996, 118, 9218-27, “Pseudo-prolines as a solubilizing, structure-disrupting protection technique in peptide synthesis.”
Dumy et al.,J. Am. Chem. Soc., 1997, 119, 918-25, “Pseudo-prolines as a molecular hinge: reversible induction of cis amide bonds into peptide backbones.”
Keller et al,J. Am. Chem. Soc., 1998, 120, 2714-20, “Enhancing the proline effect: pdeudo-prolines for tailoring cis/trans isomerization.”
Guichou Jean-François
Keller Michael
Mutter Manfred
Ruckle Thomas
Wenger Roland
Debiopharm S.A.
Low Christopher S. F.
Lukton David
Nixon & Vanderhye P.C.
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