&bgr;-polypeptide foldamers of well-defined secondary structure

Details &bgr;-polypeptide foldamers of well-defined secondary structure &bgr;-polypeptide foldamers of well-defined secondary structure

1999-12-15

2003-09-02

Celsa, Bennett (Department: 1639)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Peptides with at least one nonpeptide bond other than a...

C530S324000, C530S330000, C530S331000, C530S332000, C530S333000, C530S334000, C530S335000, C530S350000, C435S007100, C435S091500

Reexamination Certificate

active

06613876

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to &bgr;-polypeptide molecules which are oligomers and polymers of &bgr;-amino acids having stable and well-defined secondary structures, including helices and sheets, methods of generating combinatorial libraries using these &bgr;-polypeptides, and combinatorial libraries formed thereby.
DESCRIPTION OF THE PRIOR ART
Chemists have long sought to extrapolate the power of biological catalysis and recognition to synthetic systems. These efforts have focused largely on low molecular weight catalysts and receptors. Most biological systems, however, rely almost exclusively on large polymers such as proteins and RNA to perform complex chemical functions.
Proteins and RNA are unique in their ability to adopt compact, well-ordered conformations. These two biopolymers are unique also because they can perform complex chemical operations (e.g., catalysis, highly selective recognition, etc.). Folding is linked to function in both proteins and RNA because the creation of an “active site” requires proper positioning of reactive groups. Consequently, there has been a long-felt need to identify synthetic polymer backbones which display discrete and predictable folding propensities (hereinafter referred to as “foldamers”) to mimic natural biological systems. Such backbones will provide molecular “tools” to probe the functionality of large-molecule interactions (e.g. protein-protein and protein-RNA interactions).
Much work on &bgr;-amino acids and peptides synthesized therefrom has been performed by a group led by Dieter Seebach in Zurich, Switzerland. See, for example, Seebach et al. (1996)
Helv. Chim. Acta.
79:913-941: and Seebach et al. (1996)
Helv. Chim. Acta.
79:2043-2066. In the first of these two papers Seebach et al. describe the synthesis and characterization of a &bgr;-hexapeptide, namely (H-&bgr;-HVal-&bgr;-HAla-&bgr;-HLeu)
2
-OH. Interestingly, this paper specifically notes that prior art reports on the structure of &bgr;-peptides have been contradictory and “partially controversial.” In the second paper, Seebach et al. explore the secondary structure of the above-noted &bgr;-hexapeptide and the effects of residue variation on the secondary structure.
Dado and Gellman (1994)
J. Am. Chem. Soc.
116:1054-1062 describe intramolecular hydrogen bonding in derivatives of &bgr;-alanine and &ggr;-amino butyric acid. This paper postulates that &bgr;-peptides will fold in manners similar to &agr;-amino acid polymers if intramolecular hydrogen bonding between nearest neighbor amide groups on the polymer backbone is not favored.
Suhara et al. (1996)
Tetrahedron Lett.
37(10):1575-1578 report a polysaccharide analog of a &bgr;-peptide in which D-glycocylamine derivatives are linked to each other via a C-1 &bgr;-carboxylate and a C-2 &agr;-amino group. This class of compounds has been given the trivial name “carbopeptoids.”
Regarding methods to generate combinatorial libraries, several recent reviews are available. See, for instance, Ellman (1996)
Acc. Chem. Res.
29:132-143 and Lam et al. (1997)
Chem. Rev.
97:411-448.
SUMMARY OF THE INVENTION
The present invention is drawn to a genus of conformationally-restricted &bgr;-polyamides which strongly favor a helical or sheet secondary structure and which can serve as building blocks for stable tertiary structures. These stable secondary structures include helices analogous to the well-known &agr;-helical structure seen in &agr;-amino acids. Several of the subject compounds assume helical secondary structures stabilized by hydrogen bonding every 12th or 14th atom of the backbone (12-helix and 14-helix, respectively). Still other compounds according to the invention contain a “reverse turn” residue which mimics the reverse turn often seen in anti-parallel sheet structure seen in conventional peptides and proteins. These &bgr;-peptides according to the invention exhibit an anti-parallel secondary sheet structure.
More specifically, the invention is directed to &bgr;-polypeptides comprising compounds of formula:
wherein Z is a single bond or a substituent selected from the group consisting of:
and wherein when Z is a single bond, X and Y combined, together with the carbon atoms to which they are bonded, define a substituted or unsubstituted C
3
-C
8
cycloalkyl, cycloalkenyl or heterocyclic ring having one or more nitrogen atoms as the sole heteroatom, the substituents being selected from the group consisting of hydroxy, linear or branched C
1
-C
6
-alkyl, alkenyl, alkynyl; hydroxy-C
1
-C
6
-alkyl, amino-C
1
-C
6
-alkyl, C
1
-C
6
-alkyloxy, C
1
-C
6
-alkyloxy-C
1
-C
6
-alkyl, amino, mono- or di-C
1
-C
6
-alkylamino, carboxamido, carboxamido-C
1
-C
6
-alkyl, sulfonamido, sulfonamido-C
1
-C
6
-alkyl, urea, cyano, fluoro, thio, C
1
-C
6
-alkylthio, mono- or bicyclic aryl, mono- or bicyclic heteraryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C
1
-C
6
-alkyl, heteroaryl-C
1
-C
6
-alkyl, and combinations thereof; and
when Z is not a single bond, X and Y combined, together with the carbon atoms to which they are bonded, are as defined above or X and Y are independently selected from the group consisting of hydroxy, linear or branched C
1
-C
6
-alkyl, alkenyl, alkynyl; hydroxy-C
1
-C
6
-alkyl, amino-C
1
-C
6
-alkyl, C
1
-C
6
-alkyloxy, C
1
-C
6
-alkyloxy-C
1
-C
6
-alkyl, amino, mono- or di-C
1
-C
6
alkylamino, carboxamido, carboxamido-C
1
-C
6
alkyl, sulfonamido, sulfonamido-C
1
-C
6
-alkyl, urea, cyano, fluoro, thio, C
1
-C
6
-alkylthio, mono- or bicyclic aryl, mono- or bicyclic heteraryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C
1
-C
6
-alkyl, heteroaryl-C
1
-C
6
alkyl, and combinations thereof; and m, n, and p are positive integers.
The invention is also directed to an array comprising a plurality of polypeptides, the polypeptides comprising compounds of formula:
wherein Z is a single bond or a substituent selected from the group consisting of:
and wherein when Z is a single bond, X and Y combined, together with the carbon atoms to which they are bonded, define a substituted or unsubstituted C
3
-C
8
cycloalkyl, cycloalkenyl or heterocyclic ring having one or more nitrogen atoms as the sole heteroatom, the substituents being selected from the group consisting of hydroxy, linear or branched C
1
-C
6
-alkyl, alkenyl, alkynyl; hydroxy-C
1
-C
6
-alkyl, amino-C
1
-C
6
-alkyl, C
1
-C
6
-alkyloxy, C
1
-C
6
-alkyloxy-C
1
-C
6
-alkyl, amino, mono- or di-C
1
-C
6
-alkylamino, carboxamido, carboxamido-C
1
-C
6
-alkyl, sulfonamido, sulfonamido-C
1
-C
6
-alkyl, urea, cyano, fluoro, thio, C
1
-C
6
-alkylthio, mono- or bicyclic aryl, mono- or bicyclic heteraryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C
1
-C
6
-alkyl, and heteroaryl-C
1
-C
6
-alkyl; and
when Z is not a single bond, X and Y combined, together with the carbon atoms to which they are bonded, are as defined above or X and Y are independently selected from the group consisting of hydroxy, linear or branched C
1
-C
6
-alkyl, alkenyl, alkynyl; hydroxy-C
1
-C
6
-alkyl, amino-C
1
-C
6
-alkyl, C
1
-C
6
-alkyloxy, C
1
-C
6
-alkyloxy-C
1
-C
6
-alkyl, amino, mono- or di-C
1
-C
6
-alkylamino, carboxamido, carboxamido-C
1
-C
6
-alkyl, sulfonamido, sulfonamido-C
1
-C
6
-alkyl, urea, cyano, fluoro, thio, C
1
-C
6
-alkylthio, mono- or bicyclic aryl, mono- or bicyclic heteraryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C
1
-C
6
-alkyl, and heteroaryl-C
1
-C
6
-alkyl; and
m, n, and p are positive integers;
the peptides at selected, known locations on a substrate or in discrete solutions, wherein each of the polypeptides is substantially pure within each of the selected known locations or discrete solutions and has a composition which is different from other polypeptides disposed at other selected and known locations on the substrate or in other discrete solutions.
The invention is also directed to a method for preparing a combinatorial library of &bgr;-polypeptides, the method comprising at least two successive itera

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