Beta-amino acids

Abstract

Disclosed are beta-amino acid monomers containing cylcoalkyl, cycloalkenyl, and heterocylic substituents which encompass the alpha and beta carbons of the peptide backbone and beta-polypeptides made from such monomers. Method of generating combinatorial libraries of polypeptides containing the beta-peptide residues and libraries formed thereby are disclosed.

Description

[0001] This is a continuation-in-part of, and priority is hereby claimed to, application Ser. No. 09 / 464,212, filed Dec. 15, 1999, which is a divisional of Ser. No. 09 / 034,509, filed Mar. 4, 1998 (now U.S. Pat. No. 6,060,585, issued May 9, 2000), which claims priority to provisional patent application Serial No. 60 / 039,905, filed Mar. 4, 1997, the entire contents of all of which is incorporated herein.[0002] The present invention is directed to .beta.-polypeptide molecules which are oligomers and polymers of .beta.-amino acids having stable and well-defined secondary structures, including helices and sheets, methods of generating combinatorial libraries using these .beta.-polypeptides, and combinatorial libraries formed thereby.DESCRIPTION OF THE PRIOR ART[0003] 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, ho...

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Benefits of technology

[0020] The primary advantage of the present invention is that it allows the construction of synthetic peptides of known secondary structures having high conformational stability. These synthetic polyamides have utility in investigating the biological interactions involving biopolymers. The switch in helical hydrogen bond directionality between the .beta.-peptide 12- and 14-helices (See FIGS. 2A and 2B) is unprecedented among .alpha.-peptides. The residue-based conformational control offered by .beta.-peptides, which was predicted computationally, makes this class of unnatural foldamers well suited for molecular design efforts, e.g., generation of novel tertiary structures, and combinatorial searches for selective biopolymer ligands.

[0021] The .beta.-amino acid monomers are useful for constructing combinatorial libraries of compounds that display peptide behavior (because they are peptides), but resistant to enzymatic degradation because the compounds do not contain any .alpha.-peptide linkages.

[0022] As a natural consequence, the invention is further drawn to the use of these synthetic .beta.-amino acids as base molecules from which to synthesize large libraries of novel compounds utilizing the techniques of combinatorial chemistry. In addition to varying the primary sequence of the .beta.-amino acid residues, the ring positions of these compounds (and notably the equatorial positions in the cyclohexyl-rigidified .beta.-amino acids) can be substituted with a wide variety of substituents, including hydroxy, linear or branched C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyloxy, amino, mono- or di-C.sub.1-C.sub.6-alkylamino, carboxamido, sulfonamido, urea, cyano, fluoro, thio, C.sub.1-C.sub.6-alkylthio, and the like. The main advantage here is that substituents placed on the backbone rings do not substantially alter the secondary structure of the peptide. Consequently, the subject compounds can be utilized to contruct vast libraries having different substituents, but all of which share a stabilized secondary structure in both the solid state and in solution.

[0023] Thus, the .beta.-amino acids described herein are also useful for fabricating .beta.-polypeptides to model the behavior of corresponding, naturally-occurring .alpha.-polypeptide. Because the .beta.-amino acids described herein are not recognized as targets by enzymes that are specific for naturally-occurring .alpha.-polypeptides, they can be used in mechanistic studies as non-enzymatically-degradable models of the corresponding .alpha.-polypeptide.

[0024] Other aims, objects, and advantages of the invention will appear more fully from a complete reading of the following

Problems solved by technology

Interestingly, this paper specifically notes that prior art reports on the structure of .beta.-peptides have been contradictory and "partially controversial."

.beta.-Alanine oligomers, however, have been shown experimentally to be unordered in solution and to adopt sheetlike packing patterns in the solid state.

Creating discrete model systems of sheet formation using .alpha.-amino acids remains a long-standing challenge in protein science.

The difficulty lies in designing a moiety to mimic the reverse turn, thereby bringing two attached strands together to form the sheet structure without inducing uncontrolled aggregation of the bulk peptide.

A distinct disadvantage is that the reaction cannot be used to synthesize .beta.-amino acids having rings in the backbone or .alpha.-carbon substituents.

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