Sculpting the β-peptide foldamer H12 helix via a designed side-chain shape

Abstract

The long-range side-chain repulsion between the (1R,2R,3R,5R)-2-amino-6,6-dimethyl-bicyclo[3.1.1]-heptane-3-carboxylic acid (trans-ABHC) residues stabilize the H12 helix in b-peptide oligomers.Synthetic oligomers with distinct conformational preferences (foldamers) are highly intriguing compounds at the interface of covalent and supramolecular (noncovalent) chemistry. 1 Among foldamers based on remote intrastrand interactions, peptides containing b-amino acid residues are probably the most thoroughly studied systems. 2 Their versatile secondary structure patterns and the side-chain controllable conformational preferences are attracting increasing interest. 3 b-Peptide oligomers with designed molecular interaction fields have gained a number of biological applications, such as rationally designed antiviral H12 helices. 4 In these applications, the helical secondary structures (H14, H12 and H10/12) play crucial roles with regard to the biological activity; they are induced by the special substitution and stereochemical pattern of the b-peptide backbone, while the side-chain chemistry is varied independently. The stabilization effects of b-amino acid residues with cyclic side-chains are indispensable in the b-peptide helix design. The H12 helix, which is a good mimic of the a-helix in terms of overall shape, can be stabilized by the incorporation of a sufficient number of trans-2-aminocyclopentanecarboxylic acid (trans-ACPC) or the structurally related trans-amino-pyrrolidinecarboxylic acid (trans-APC) residues in the sequence. 5 Two-thirds of the residues are required to have the side chain topology of a five-membered ring with a trans relative backbone configuration in order to gain a reasonably stable H12 helix, which imposes considerable limitations on the chemical diversity of the side-chain pattern along these b-peptide helices. Independent methods to stabilize the H12 helix are therefore still sought. 6 In the present work, a novel approach is proposed whereby to induce formation of the H12 helix. The steric repulsion between the side-chains in positions i and (i+3) was utilized to bias the potential energy landscape, which eventually destabilizes the H14 helix in favor of the H12 helix. We demonstrate here that bulky trans-ABHC residues retain the helical organization of the peptide chain, and the designed interactions facilitate formation of the H12 helix.Construction of a H14 helix, the b-peptide secondary structure most often utilized in biomedical studies, can readily be achieved by using b 3 -substituted b-amino acids in combination with trans-2-aminocyclohexanecarboxylic acids (trans-ACHCs). 7 The cyclic side-chain of the latter lends extra stability to the secondary structure through the restricted conformational space and the i-(i+3) hydrophobic stacking interactions between the cyclohexane rings. 8 Recent results led to the successful synthesis of monoterpene-derived b-amino acids with an apopinane skeleton (2-amino-6,6-dimethyl-bicyclo[3.1.1]heptane-3-carboxylic acid; ABHC). 9 The apopinane moiet...

C11/C9 Helical Folding in αβ Hybrid Peptides Containing 1‐Amino‐cyclohexane acetic acid (β3, 3‐Ac6c)

“…The oligomers of trans ‐cyclic β‐amino acids may promote C 10 ‐, C 12 ‐, or C 14 ‐helical structures . In addition, four‐membered cis ‐oxetane‐based and trans ‐cyclobutane‐based β‐residues promote 10‐ and 12‐helices, respectively . The NMR‐spectroscopic studies of oligo‐β‐peptides with alternating acyclic monosubstituted β 2 ‐ and β 3 ‐amino acids established the mixed helices with C 10 /C 12 hydrogen bonds .…”

High-performance liquid chromatographic enantioseparation of monoterpene-based 2-amino carboxylic acids on macrocyclic glycopeptide-based phases

“…Also, they were used successfully as chiral auxiliaries in the enantioselective reactions of Et 2 Zn with aromatic aldehydes [10,12,8,9]. Apopinane-based ␤-amino acids were used as building blocks in the construction of stable H12 foldameric helices and in Ugi four-centre three-component reactions [11,13,14]. The latter new family of monoterpene-based chiral ␤-lactams and ␤-amino acid derivatives derived from (−)-and (+)-apopinene recently were reported to eliminate the disadvantageous steric effect of the methyl substituent on the pinane ring system [11].…”

Evaluation of an aza-Michael approach for the synthesis of 3,3-dimethyl-2-aminocyclobutane-1-carboxylic acid

“…Thus, Fülöp and co-workers recently demonstrated that oligomers of a monoterpene-derived trans-β-AA, notionally a sterically challenged ACHC analog, preferred to adopt a 12-helix conformation in order to avoid long-range side-chain repulsions. 7 In an effort to expand the set of available ring-substituted cyclic β-AAs, we envisaged the preparation of trans-3,3-dimethyl-2-aminocyclobutane-1-carboxylic acid 1 (Figure 1). This compound is a sterically-congested derivative of ACBC, but can also be viewed as a conformationally constrained analog of the β 2 -AA 2-aminomethyl-4-methylpentanoic acid 2, or of the β 3 -AA β-homovaline 3, both of which have been incorporated into designed β-peptide sequences.…”