Helices in peptoids of α- and β-peptides

Baldauf, Carsten; Günther, Robert; Hofmann, Hans‐Jörg

doi:10.1088/1478-3975/3/1/s01

Cited by 67 publications

(80 citation statements)

References 54 publications

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“…A number of years later, computational simulation of β-peptoids provided support of the existence of low energy conformations corresponding to helical oligomers displaying either all cis-or all trans-amide bonds. 19 However, two following circular dichroism (CD) studies provided ambiguous conclusions regarding folding due to the lack of high-resolution structural data. 20,21 In response to the initial difficulties in achieving robustly folded conformers, we decided to pursue peptide/β-peptoid hybrids to include the hydrogen bonding capability of the α-amino acids as well as easy access to oligomers by dimer coupling on solid-phase.…”

Section: Introductionmentioning

confidence: 99%

β-Peptoid Foldamers at Last

2015

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For a long time, peptides were considered unsuitable for drug development due to their inherently poor pharmacokinetic properties and proteolytic susceptibility. However, this paradigm has changed significantly in the past decade with the approval of numerous antibodies and proteins as drugs. In parallel, research in the field of synthetic molecules that are able to mimic or complement folding patterns exhibited by biopolymers, but are not recognized by proteases, have received considerable attention as well. Such entities were coined "foldamers" by Professor Gellman in an Account published in this journal in the late 1990s. Oligomers of N-alkylated 3-aminopropionic acid residues have been called β-peptoids due to their structural similarity to β-peptides and peptoids (N-alkylglycines), respectively. Because bona fide foldamer behavior has been demonstrated for both parent architectures, we wondered if the β-peptoids could serve as a successful addition to the known ensemble of peptidomimetic foldamers. When we entered this field, only the seminal description of libraries of β-peptoid dimers and trimers by Hamper et al. had been published a number of years earlier [ J. Org. Chem. 1998 , 63 , 708 ]. Perhaps somewhat naïvely in retrospect, we envisioned that elongation of chain length combined with introduction of bulky α-chiral side chains would deliver folded structures as reported for the α-peptoid counterparts. Initially, we, and others, were unsucessful in obtaining stable secondary structures of β-peptoid oligomers, and instead, these residues were either incorporated in cyclic structures or in combination with other types of residues to give peptidomimetic constructs with heterogeneous backbones. Amphiphilic architectures with various membrane-targeting activities, such as mimics of antimicrobial peptides or cell-penetrating peptides, have thus been particularly successful. Introduction of β-peptoid residues in histone deacetylase inhibitors mimicking nonribosomal cyclotetrapeptides have also been reported. In the present Account, we will sketch the scientific journey that ultimately delivered robustly folded β-peptoid oligomers. Contributions involving biological evaluation of peptidomimetic constructs containing β-peptoid residues, as mentioned above, which were investigated leading up to these recently reported high-resolution helical structures, will thus be discussed. On the basis of the work described in this Account, we envision that β-peptoids will find future utility as peptidomimetics for biomedical investigation containing both heterogeneous and homogeneous backbones. The recent demonstration of control over the secondary structure of a homogeneous β-peptoid backbone now enables structure-based design of scaffolds with predictable display of desired functionalities in three dimensions.

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Section: Introductionmentioning

confidence: 99%

β-Peptoid Foldamers at Last

2015

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“…While polypeptides adopt secondary structures (e.g., helix or sheet) that are stabilized by intra- or intermolecular hydrogen bonding, the folding of polypeptoids into well-defined secondary structures is dictated by side chain stereoelectronic effects. 24,29–33 Studies conducted on oligomericpeptoids (n < 20) have demonstrated their biocompatibility, enhanced enzymatic stability 34 – 36 and cell permeability relative to polypeptides. 37 They have been extensively investigated for biological and therapeutic applications.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Amphiphilic Cyclic Diblock Copolypeptoids from N-Heterocyclic Carbene-Mediated Zwitterionic Polymerization of N-Substituted N-Carboxyanhydride

et al. 2011

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N-Heterocyclic carbene (NHC)-mediated ring-opening polymerization of N-decylN-carboxylanhydride monomer (De-NCA) has been shown to occur in a controlled manner, yielding cyclic poly(N-decyl-glycine)s (c-PNDGs) with polymer molecular weights (MW) between 4.8 and 31 kg·mol−1 and narrow molecular weight distributions (PDI < 1.15). The reaction exhibits pseudo-first order kinetics with respect to monomer concentration. The polymer MW increases linearly with conversion, consistent with a living polymerization. ESI MS and SEC analysesconfirm the cyclic architectures of the forming polymers. DSC and WAXS studies reveal that the c-PNDG homopolymers are highly crystalline with two prominent first order transitions at 72–79°C (Tm,1) and 166–177°C (Tm,2), which have been attributed to the side chain and main chain melting respectively. A series of amphiphilic cyclic diblock copolypeptoids [i.e.,poly(N-methyl-glycine)-b-poly(N-decyl-glycine) (c-PNMG-b-PNDG)] with variable molecular weight and composition was synthesized by sequential NHC-mediated polymerization of the corresponding N-methyl N-carboxyanhydride (Me-NCA) and De-NCA monomers. 1H NMR analysis reveals that adjusting the initial monomer to NHC molar ratio can readily control the block copolymer chain length and composition. Time-lapsed light scattering and cryogenic transmission electron microscopy (cryo-TEM) analysis of c-PNDG-b-PNMG samples revealed that the amphiphilic cyclic block copolypeptoids self-assemble into spherical micelles that reorganize into micron-long cylindrical micelles with uniform diameter in room temperature methanol over the course of several days. An identical morphological transition has also been noted for the linear analogs, which occurs more rapidly than for the cyclic copolypeptoids. We tentatively attribute this difference to the different crystallization kinetics of the solvophobic block (i.e., PNDG) in the cyclic and linear block copolypeptoids.

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“…The amide bond geometry in both unblocked and blocked poly-sarcosine peptoids 23 has been reported to be trans [24]. Peptoids are generally synthesized by coupling a haloacetic acid and a primary amine by using DMF or DMSO as solvents [25].…”

Section: Introductionmentioning

confidence: 99%

Structural Modeling and Conformational Analysis of Aromatic Polypeptoid Models Confined to Different Environmental Conditions

Saini¹,

Nandel²

2016

IJCA

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Conformations of achiral and chiral aromatic homopolypeptoids of Nphe, Nspe and Nrpe were studied by quantum mechanics and molecular dynamics approaches. The amide bond geometry in model peptoids Ac-X-NMe 2 could be both cis and trans and the Nphe peptoids adopted degenerate conformations of opposite handedness with Φ, Ψ values of ~ ± 120º, ± 150º with trans amide bond geometry. This degeneracy was lifted with increase in chain length; in favor of the structure with Φ = -120º, Ψ = -150º. Polypeptoids of Nspe and Nrpe with and without protecting groups populated states with Φ, Ψ values of ~ 110º, 155º & -110º, -165º respectively with trans amide bond geometry.Simulation studies in water revealed that with protecting groups peptoid Ac-(Nspe/Nrpe) 5 -NMe 2 populated with cis amide bond geometry in PP type I and inverse PP type I helices respectively due to interactions between the solvent molecules and carbonyl oxygens of the backbone. Without protecting groups these polypeptoids populated poly-Lproline type II conformations. In DMSO these peptoids were shown to populate in PP type-I and inverse PP type-I helices and without protecting groups they could be realized in PP type-I as well as inverse PP type-I conformation whereas the peptoid -Nrpe 6 -NH 2 could be realized in inverse PP type-I conformation. Analysis of simulation results as a function of time ruled out amide bond inter-conversions between cis and trans geometry. Hence, like polyproline peptoids can also be exploited as molecular spacers.

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Helices in peptoids of α- and β-peptides

Cited by 67 publications

References 54 publications

β-Peptoid Foldamers at Last

β-Peptoid Foldamers at Last

Synthesis and Characterization of Amphiphilic Cyclic Diblock Copolypeptoids from N-Heterocyclic Carbene-Mediated Zwitterionic Polymerization of N-Substituted N-Carboxyanhydride

Structural Modeling and Conformational Analysis of Aromatic Polypeptoid Models Confined to Different Environmental Conditions

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