12/10-Helix in Mixed β-Peptides Alternating Bicyclic and Acyclic β-Amino Acids: Probing the Relationship between Bicyclic Side Chain and Helix Stability.

12/10-Helices constitute suitable templates that can be used to design original structures. Nevertheless, they often suffer from a weak stability in polar solvents because they exhibit a mixed hydrogen-bond network resulting in a small macrodipole. In this work, stable and functionalizable 12/10-helices were developed by alternating a highly constrained β2, 3, 3 -trisubstituted bicyclic amino acid (S)-1-aminobicyclo[2.2.2]octane-2-carboxylic acid ((S)-ABOC) and an acyclic substituted β-homologated proteinogenic amino acid (l-β3 -hAA). Based on NMR spectroscopic analysis, it was shown that such mixed β-peptides display well-defined right-handed 12/10-helices in polar, apolar, and chaotropic solvents; that are, CD3 OH, CDCl3 , and [D6 ]DMSO, respectively. The stability of the hydrogen bonds forming the C10 and C12 pseudocycles as well as the benefit provided by the use of the constrained bicyclic ABOC versus typical acyclic β-amino acids sequences when designing 12/10-helix were investigated using NH/ND NMR exchange experiments and DFT calculations in various solvents. These studies showed that the β3 -hAA/(S)-ABOC helix displayed a more stable hydrogen-bond network through specific stabilization of the C10 pseudocycles involving the bridgehead NH of the ABOC bicyclic scaffold.

[1]  H. Hofmann,et al.  Modulating the Structural Properties of α,γ-Hybrid Peptides by α-Amino Acid Residues: Uniform 12-Helix Versus "Mixed" 12/10-Helix. , 2017, Chemistry.

[2]  T. Martinek,et al.  De Novo Modular Development of a Foldameric Protein–Protein Interaction Inhibitor for Separate Hot Spots: A Dynamic Covalent Assembly Approach , 2017, ChemistryOpen.

[3]  K. Kulkarni,et al.  Unique Functional Materials Derived from β-Amino Acid Oligomers , 2017 .

[4]  H. Hofmann,et al.  Solvent-Directed Switch of a Left-Handed 10/12-Helix into a Right-Handed 12/10-Helix in Mixed β-Peptides. , 2017, The Journal of organic chemistry.

[5]  Y. Kang,et al.  12/10-Helical β-Peptide with Dynamic Folding Propensity: Coexistence of Right- and Left-Handed Helices in an Enantiomeric Foldamer. , 2016, Journal of the American Chemical Society.

[6]  Jean Martínez,et al.  12/14/14-Helix Formation in 2:1 α/β-Hybrid Peptides Containing Bicyclo[2.2.2]octane Ring Constraints. , 2016, Chemistry.

[7]  S. Gellman,et al.  Effects of Single α-to-β Residue Replacements on Structure and Stability in a Small Protein: Insights from Quasiracemic Crystallization. , 2016, Journal of the American Chemical Society.

[8]  P. Perlmutter,et al.  Geometrically Precise Building Blocks: the Self-Assembly of β-Peptides. , 2015, Chemistry & biology.

[9]  R. Guillot,et al.  Fine Tuning of β-Peptide Foldamers: a Single Atom Replacement Holds Back the Switch from an 8-Helix to a 12-Helix. , 2015, Angewandte Chemie.

[10]  Brian F. Fisher,et al.  Heterogeneous H-bonding in a foldamer helix. , 2015, Journal of the American Chemical Society.

[11]  D. Seebach,et al.  Interaction of β3/β2‐Peptides, Consisting of Val‐Ala‐Leu Segments, with POPC Giant Unilamellar Vesicles (GUVs) and White Blood Cancer Cells (U937) – A New Type of Cell‐Penetrating Peptides, and a Surprising Chain‐Length Dependence of Their Vesicle‐ and Cell‐Lysing Activity , 2015, Chemistry & biodiversity.

[12]  Jean Martínez,et al.  Unprecedented chain-length-dependent conformational conversion between 11/9 and 18/16 helix in α/β-hybrid peptides. , 2014, Angewandte Chemie.

[13]  C. Cabrele,et al.  Peptides containing β-amino acid patterns: challenges and successes in medicinal chemistry. , 2014, Journal of medicinal chemistry.

[14]  Sean P. Palecek,et al.  Hydrophobicity and Helicity Regulate the Antifungal Activity of 14-Helical β-Peptides , 2014, ACS chemical biology.

[15]  I. Mándity,et al.  Exploiting aromatic interactions for β-peptide foldamer helix stabilization: a significant design element. , 2014, Chemistry.

[16]  Jean Martínez,et al.  Mixed oligoureas based on constrained bicyclic and acyclic β-amino acids derivatives: on the significance of the subunit configuration for folding. , 2013, Chemistry.

[17]  I. Mándity,et al.  Foldameric β-H18/20P Mixed Helix Stabilized by Head-to-Tail Contacts: A Way to Higher-Order Structures , 2013 .

[18]  T. Iwatsubo,et al.  Effect of helical conformation and side chain structure on γ-secretase inhibition by β-peptide foldamers: insight into substrate recognition. , 2013, Journal of medicinal chemistry.

[19]  Deepak Chatterjee,et al.  Synthesis of C-linked carbo-β2-amino acids and β2-peptides: design of new motifs for left-handed 12/10- and 10/12-mixed helices. , 2012, Organic & biomolecular chemistry.

[20]  F. Fülöp,et al.  Self-association-driven transition of the β-peptidic H12 helix to the H18 helix. , 2012, Organic & biomolecular chemistry.

[21]  F. Fülöp,et al.  Peptidic foldamers: ramping up diversity. , 2012, Chemical Society reviews.

[22]  Scott J. Shandler,et al.  Environment- and sequence-dependence of helical type in membrane-spanning peptides composed of β3-amino acids. , 2011, Organic letters.

[23]  P. Balaram,et al.  Structural chemistry of peptides containing backbone expanded amino acid residues: conformational features of β, γ, and hybrid peptides. , 2011, Chemical reviews.

[24]  I. Mándity,et al.  Building β-peptide H10/12 foldamer helices with six-membered cyclic side-chains: fine-tuning of folding and self-assembly. , 2010, Organic letters.

[25]  Lara C. Spencer,et al.  Crystallographic characterization of 12-helical secondary structure in β-peptides containing side chain groups. , 2010, Journal of the American Chemical Society.

[26]  R. Guillot,et al.  12-Helix folding of cyclobutane beta-amino acid oligomers. , 2010, Organic letters.

[27]  S. Chandrasekhar,et al.  Backbone regulation mimicry by beta-peptidic foldamers: formation of a 10-helix in a mixed 6-strand/14-helix conformational pool. , 2009, Chemistry.

[28]  I. Mándity,et al.  Sculpting the beta-peptide foldamer H12 helix via a designed side-chain shape. , 2009, Chemical communications.

[29]  K. S. Rao,et al.  Synthesis of beta-peptides with beta-helices from new C-linked carbo-beta-amino acids: study on the impact of carbohydrate side chains. , 2009, Chemistry, an Asian journal.

[30]  W. Han,et al.  Theoretical analysis of secondary structures of beta-peptides. , 2008, Accounts of chemical research.

[31]  S. Gellman,et al.  Comparison of Design Strategies for Promotion of β‐Peptide 14‐Helix Stability in Water , 2008, Chembiochem : a European journal of chemical biology.

[32]  James Gardiner,et al.  Beta-peptidic peptidomimetics. , 2008, Accounts of chemical research.

[33]  Jean Martínez,et al.  Asymmetric Diels–Alder Cycloaddition of 1‐Aminocyclohexadiene to Chiral Acrylate: Synthesis of Enantiopure Bridgehead‐Aminobicyclo[2.2.2]octane‐2‐carboxylic Acid Derivatives , 2007 .

[34]  Scott J. Shandler,et al.  Foldamers as versatile frameworks for the design and evolution of function. , 2007, Nature chemical biology.

[35]  M. Hollósi,et al.  Effects of the alternating backbone configuration on the secondary structure and self-assembly of beta-peptides. , 2006, Journal of the American Chemical Society.

[36]  Amy J. Karlsson,et al.  Antifungal Activity from 14-Helical β-Peptides , 2006 .

[37]  S. Chandrasekhar,et al.  Expanding the conformational pool of cis-β-sugar amino acid: accommodation of β-hGly motif in robust 14-helix , 2005 .

[38]  C. Baldauf,et al.  Side‐chain control of folding of the homologous α‐, β‐, and γ‐peptides into “mixed” helices (β‐helices) , 2005 .

[39]  S. Chandrasekhar,et al.  Formation of a stable 14-helix in short oligomers of furanoid cis-beta-sugar-amino acid. , 2004, Journal of the American Chemical Society.

[40]  D. Seebach,et al.  The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components , 2004 .

[41]  E. Giralt,et al.  14-Helical folding in a cyclobutane-containing β-tetrapeptide , 2004 .

[42]  R. Günther,et al.  Gemischte Helices – ein allgemeines Faltungsmuster in homologen Peptiden? , 2004 .

[43]  C. Baldauf,et al.  Mixed helices--a general folding pattern in homologous peptides? , 2004, Angewandte Chemie.

[44]  B. Jagannadh,et al.  Robust mixed 10/12 helices promoted by "alternating chirality" in a new family of C-linked carbo-beta-peptides. , 2003, Journal of the American Chemical Society.

[45]  Ferenc Fülöp,et al.  Side-chain control of beta-peptide secondary structures. , 2003, European journal of biochemistry.

[46]  Jin-seong Park,et al.  Accommodation of α-Substituted Residues in the β-Peptide 12-Helix: Expanding the Range of Substitution Patterns Available to a Foldamer Scaffold , 2003 .

[47]  D. Seebach,et al.  Die vierte helicale Sekundärstruktur von β‐Peptiden: (P)‐28‐Helix eines β‐Hexapeptids aus (2R,3S)‐3‐Amino‐2‐hydroxycarbonsäure‐Einheiten , 2003 .

[48]  B. Jaun,et al.  The fourth helical secondary structure of β-peptides: The (P)-28-helix of a β-hexapeptide consisting of (2R,3S)-3-amino-2-hydroxy acid residues , 2003 .

[49]  H. Kessler,et al.  Design, synthesis, and NMR structure of linear and cyclic oligomers containing novel furanoid sugar amino acids. , 2002, Chemistry.

[50]  S. Gellman,et al.  Structure-activity studies of 14-helical antimicrobial beta-peptides: probing the relationship between conformational stability and antimicrobial potency. , 2002, Journal of the American Chemical Society.

[51]  S. Gellman,et al.  Stereoselective synthesis of 3-substituted 2-aminocyclopentanecarboxylic acid derivatives and their incorporation into short 12-helical beta-peptides that fold in water. , 2002, Journal of the American Chemical Society.

[52]  B. Jaun,et al.  Mixed β2/β3-Hexapeptides and β2/β3-Nonapeptides Folding to (P)-Helices with Alternating Twelve- and Ten-Membered Hydrogen-Bonded Rings , 2002 .

[53]  H. Hofmann,et al.  Theoretical Prediction of Substituent Effects on the Intrinsic Folding Properties of β-Peptides , 2002 .

[54]  S. Gellman,et al.  Tolerance of acyclic residues in the beta-peptide 12-helix: access to diverse side-chain arrays for biological applications. , 2002, Journal of the American Chemical Society.

[55]  Matthew J. Mio,et al.  A field guide to foldamers. , 2001, Chemical reviews.

[56]  W. DeGrado,et al.  beta-Peptides: from structure to function. , 2001, Chemical reviews.

[57]  J. Goodman,et al.  10-Helical conformations in oxetane β-amino acid hexamers , 2001 .

[58]  S. Gellman,et al.  Solution Conformations of Helix-Forming β-Amino Acid Homooligomers , 2000 .

[59]  M. Thormann,et al.  Basic conformers in beta-peptides. , 1999, Biopolymers.

[60]  I. Karle,et al.  Synthesis and Characterization of trans-2-Aminocyclohexanecarboxylic Acid Oligomers: An Unnatural Helical Secondary Structure and Implications for β-Peptide Tertiary Structure , 1999 .

[61]  B. Jaun,et al.  β2‐ and β3‐Peptides with Proteinaceous Side Chains: Synthesis and solution structures of constitutional isomers, a novel helical secondary structure and the influence of solvation and hydrophobic interactions on folding , 1998 .

[62]  B. Jaun,et al.  "Mixed" β-peptides. A unique helical secondary structure in solution. Preliminary communication , 1997 .

[63]  D. Seebach,et al.  β-Peptides: a surprise at every turn , 1997 .

[64]  Samuel H. Gellman,et al.  β-Peptide Foldamers: Robust Helix Formation in a New Family of β-Amino Acid Oligomers , 1996 .

[65]  B. Jaun,et al.  Probing the Helical Secondary Structure of Short‐Chain β‐Peptides , 1996 .

[66]  Jean Martínez,et al.  N-benzhydryl-glycolamide esters (OBg esters) as carboxyl protecting groups in pept1de synthesis , 1988 .