Chiral N-substituted glycines can form stable helical conformations

Armand, Philippe; Kirshenbaum, Kent; Falicov, Alexis; Dunbrack, Roland L.; Dill, Ken A.; Zuckermann, Ronald N.; Cohen, Fred E.

doi:10.1016/s1359-0278(97)00051-5

Cited by 180 publications

(295 citation statements)

References 12 publications

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“…The poly-N-substituted glycine structure of peptoids precludes both backbone chirality and intrachain hydrogen bonding; nevertheless, peptoids can be driven to form helical secondary structures via a periodic incorporation of bulky, ␣-chiral side chains (37)(38)(39)(40). Previous work has shown that incorporation of homochiral side chains can give rise to polyproline type-I-like helices with a periodicity of approximately three monomers per turn and a helical pitch of 6.0-6.7 Å (37-39, 41, 42).…”

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confidence: 99%

Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides

Chongsiriwatana¹,

Patch²,

Czyzewski³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

568

578

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Antimicrobial peptides (AMPs) and their mimics are emerging as promising antibiotic agents. We present a library of ''ampetoids'' (antimicrobial peptoid oligomers) with helical structures and biomimetic sequences, several members of which have low-micromolar antimicrobial activities, similar to cationic AMPs like pexiganan. Broad-spectrum activity against six clinically relevant BSL2 pathogens is also shown. This comprehensive structure-activity relationship study, including circular dichroism spectroscopy, minimum inhibitory concentration assays, hemolysis and mammalian cell toxicity studies, and specular x-ray reflectivity measurements shows that the in vitro activities of ampetoids are strikingly similar to those of AMPs themselves, suggesting a strong mechanistic analogy. The ampetoids' antibacterial activity, coupled with their low cytotoxicity against mammalian cells, make them a promising class of antimicrobials for biomedical applications. Peptoids are biostable, with a protease-resistant N-substituted glycine backbone, and their sequences are highly tunable, because an extensive diversity of side chains can be incorporated via facile solid-phase synthesis. Our findings add to the growing evidence that nonnatural foldamers will emerge as an important class of therapeutics.antibiotics ͉ peptidomimetics ͉ structure-activity studies N atural antimicrobial peptides (AMPs) defend a wide array of organisms against bacterial pathogens and show potential as supplements for or replacements of conventional antibiotics, because few bacteria have evolved resistance to them (1-3). Many AMPs kill bacteria by permeabilization of the cytoplasmic membrane, causing depolarization, leakage, and death (4), whereas others target additional anionic bacterial constituents (e.g., DNA, RNA, or cell wall components) (2, 5). Amphipathic secondary structures in which residues are segregated into hydrophobic and cationic regions ( Fig. 1 A and B) are the hallmark of most AMPs (6). Regardless of their final target of killing, AMPs must interact with the bacterial cytoplasmic membrane, and their amphipathicity is integral to such interactions (1, 2, 7). Additionally, their cationic nature imparts AMPs with some measure of selectivity, because mammalian cell membranes are largely zwitterionic. The precise nature of AMP-membrane interactions remains controversial and actively debated; a variety of mechanisms have been proposed, including the carpet (4), barrel-stave pore (4), toroidal pore (8), and aggregate (9) models. Nevertheless, a considerable number of structure-activity investigations have elucidated how the physicochemical properties of these molecules relate to their biological activities (4,7,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).Although AMPs have been actively studied for decades (23-25), they have yet to see widespread clinical use (1). This is due in part to the vulnerability of many peptide therapeutics to rapid in vivo degradation, which dramatically reduces their bioavailability. Nonnatural mimics of AMPs...

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mentioning

confidence: 99%

Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides

Chongsiriwatana¹,

Patch²,

Czyzewski³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

568

578

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“…This change makes peptoids protease resistant (24), thereby increasing their bioavailability. Peptoids with ␣-chiral side chains can fold into three-sided polyproline type-I-like helices that are ideal for mimicking the amphipathic nature of many AMPs (2,3,16,36,37). The cost-effective and facile synthesis of peptoids (38), as well as their designable structure and advantageous pharmacological properties, makes peptoids excellent candidates to mimic antimicrobial peptides.…”

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confidence: 99%

Short Alkylated Peptoid Mimics of Antimicrobial Lipopeptides

Chongsiriwatana

Miller

Wetzler

et al. 2011

Antimicrob Agents Chemother

107

127

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We report the creation of alkylated poly-N-substituted glycine (peptoid) mimics of antimicrobial lipopeptides with alkyl tails ranging from 5 to 13 carbons. In several cases, alkylation significantly improved the selectivity of the peptoids with no loss in antimicrobial potency. Using this technique, we synthesized an antimicrobial peptoid only 5 monomers in length with selective, broad-spectrum antimicrobial activity as potent as previously reported dodecameric peptoids and the antimicrobial peptide pexiganan.

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“…Sarcosine, the simplest peptoid with minimal steric restrictions occurs in some natural proteins and polypeptides [22], surface grafted polysarcosine can be used as antifouling polymer brushes [23]. The amide bond geometry in both unblocked and blocked poly-sarcosine peptoids 23 has been reported to be trans [24].…”

Section: Introductionmentioning

confidence: 99%

“…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%

“…Peptoids are generally synthesized by coupling a haloacetic acid and a primary amine by using DMF or DMSO as solvents [25]. Due to the hydrophobic nature of peptoids compared to the corresponding amino acids they are difficult to crystallize and their structural studies have mainly been carried out by circular dichroism-a low resolution technique and NMR spectroscopy [23,[26][27][28][29][30][31]. Also, crystallographic studies are mostly on cyclic peptoids and there are only a few studies on linear peptoids [32][33][34][35][36].…”

Section: Introductionmentioning

confidence: 99%

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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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Chiral N-substituted glycines can form stable helical conformations

Abstract: Peptoid oligomers containing chiral centers in their sidechains present a new structural paradigm that has promising implications for the design of stably folded molecules. We expect that their novel structure may provide a scaffold to create heteropolymers with useful functionality.

Cited by 180 publications

References 12 publications

Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides

Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides

Short Alkylated Peptoid Mimics of Antimicrobial Lipopeptides

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

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