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The C-linked carbo-beta-peptides, oligomers of a new class of C-linked carbo-beta3-amino acids, have been shown to generate mixed 12/10 and 10/12 helices. The design involves use of "alternating chirality" of the epimeric (at the amine center) monomers to control the stability of these helices. The observation of stable 12/10 helix in a tripeptide and 10/12 helix in a tetrapeptide is unprecedented.

General. Solvents for extraction: ACS grade. Solvents for reaction: reagent grade. Reagents: unless otherwise noted, from Acros, Fluka, or Aldrich, highest quality available. TLC: silica gel 60 F 254 aluminum plates, (Whatman, type Al Sil G/UV, 250 µm layer); visualization by UV absorption) and/or by dipping in a soln. anisaldehyde/H 2 SO 4 /AcOH/EtOH 5:5:1:18) cerium(IV)sulfate (3 mM)/ammonium molybdate (250 mM) in aq. H 2 SO 4 (10%); followed by heating. Flash column chromatography (CC) was performed on silica gel 60 (0.40-0.63 mm, 230-440 mesh, EM Science) at low pressure (max. 2 bar). Melting points (uncorrected) MEL-TEMP II (Laboratory Devices Inc., USA). NMR: 1 H: δ values in ppm (TMS as internal standard); J [Hz], assignments of 1 H resonances were in some cases based on 2D experiments (1 H, 1 H-COSY); 13 C: δ values in ppm (TMS as internal standard); J [Hz]; assignments and multiplicities were based on 2D experiments (1 H, 13 C-COSY). ESI-MS (mode): m/z (intensity in %); performed with Micromat-LCT. Matrix-assisted laser-desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was performed on a Voyager-Elite mass spectrometer (Perseptive Biosystems) with delayed extraction with THAP or DHB as the matrix with ammonium citrate added to the sample. Oligo-dipeptides were synthesized on an Expedite 8909 Nucleic Acid Synthesis system (Perseptive Biosystems) in the PNA mode with the following modifications: 0.14M dipeptide monomer in NMP/DMSO 4:1; 0.13M of HATU in NMP; washing soln. A: NMP/DMSO 4:1; washing soln. B: NMP/DMSO 4:1; deblocking soln. 30% piperidine in NMP/DMSO 4:1; capping: 5% Ac 2 O, 6% lutidine in NMP/DMSO 4:1; base-mixture: 0.14M DIPEA, 0.21M lutidine in NMP; coupling time of 30 min; in some cases double coupling step was used. Coupling efficiency was calculated by Fmoc-assay. For a majority of the synthesis, the average coupling efficiency was greater than 95%. HPLC purification of oligopeptides was achieved either by (a) ion-exchange: with MONO-Q HR 5/5 Pharmacia, 10 Ï 0.5 cm or Nucleogen-DEAE 60-7 Machery Nagel, 125 Ï 4, flow 1 ml / min; mobile phase: eluant A: 10 mM Na 2 HPO 4 , H 2 O, pH 11.5 (unless otherwise specified); eluant B: 10 mM Na 2 HPO 4 , 1 M NaCl, H 2 O, pH 11.5 (unless otherwise specified); or with Nucleogen-DEAE 60-7 Machery Nagel, 125 Ï 4, flow 1 ml / min, mobile phase: eluant A: 10 mM Na 2 HPO 4 , H 2 O, pH 7.0; eluant B: 10 mM Na 2 HPO 4 , 1 M NaCl, H 2 O, pH 7.0 or by (b) reverse-phase: Aquapore ODS 20 micron Brownlee, 250 Ï 10.0 mm, flow 4 ml / min. Mobile phase: eluant A: 0.1% TFA in H 2 O; eluant B: 0.1% TFA in MeCN. UV Spectra were recorded on a Cary 1 C

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For digestion of starch, α‐amylase first hydrolyzes the starch structure to α‐limit dextrins (αLDx's). Complete hydrolysis to glucose then takes place through the combined action of mucosal maltase‐glucoamylase (MGAM) and sucrase‐isomaltase (SI), which have two subunits each (N‐ and C‐ terminal). In this study, we applied the concept of “toggling” through differential inhibition of subunits to examine control of glucogenesis from αLDx's with the aim of attaining slow glucose delivery to the body. Mammalian recombinant MGAM and SI subunits were individually reacted with αLDx's with varying concentrations of acarbose, a well known α‐glucosidase inhibitor. Released glucose amounts were analyzed for hydrolysis activity. Notably, results showed selective inhibitory effect on C‐terminal subunits by acarbose for starch digestion. Furthermore, Ki values of C‐terminal subunits were lower than human α‐amylases which can be applied that certain amount of acarbose had inhibitory effect on the hydrolysis of αLDx's by C‐terminal subunits but not on α‐amylase for moderating glucogenesis. This result supports the concept of controlling starch digestion rate for slow glucose release through the “toggling” of activities of the mucosal α‐glucosidases by selective enzyme inhibition. Conceivably this approach could be used to treat Type II diabetes by extending postprandial blood glucose delivery to the body, and may apply as well to other metabolic syndrome‐associated diseases and conditions. This research was supported from Whistler Center for Carbohydrate Research and USDA/AFRI.

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Synthetic oligomers of b-amino acids, that is, b-peptides, [1] are amongst the most studied class of molecules in foldamer chemistry. Changes in their substitution pattern generate a variety of interesting structural features in these molecules, [2][3][4][5] which have thus begun to prove immensely useful in bioactive peptide mimicry.[6] Amongst the various peptide secondary structures, mixed helices are unique to b-peptides. These structures contain intertwined 12 and 10-membered Hbonded rings and are unprecedented in a-proteins. Seebach et al. [4a] were the first to demonstrate the existence of righthanded 12/10 mixed helical structures in b-peptides with alternating b 2 and b 3 residues. Kessler and co-workers [4b] have reported such structures in mixed peptides containing constrained f-sugar amino acid and b-hGly repeats. We recently reported [7] the formation of both 10/12 and 12/10 right-handed helices by b-peptides derived from C-linked carbo-b 3 -amino acids (Caa) with "alternating chirality." Although a variety of helical structures have been discovered in b-peptides, no reports have been published in this active area of research that describe left-handed mixed helices. Several natural proteins [8] have been found to contain small fragments of left-handed helices, most of which occur in or near an active or binding site and are thus likely to be of functional importance. Herein, we report the design, synthesis, and structural study of "mixed b-peptides" with right-handed and novel left-handed mixed (10/12 and 12/10) helical structures. These peptides are derived from alternating epimeric Clinked carbo-b 3 -amino acids [9] (1 or 2; Scheme 1) and b-hGly units.Our previous study revealed that Caa 1 occupies an energetically unfavorable position in the carbo-b-peptides 3 and 4, [7] although robust mixed helical structures were formed by these peptides. We envisaged a new design intended to provide more conformational freedom and relieve steric strain [10,11] through the inclusion of alternating Caa (1 or 2) and b-hGly residues. Mixed b-peptides 5-12 (5/6 and 7/8 with Caa 2 and 1 at the N terminus, respectively; 9/10 and 11/12 with b-hGly at the N terminus) were prepared by conventional procedures (1-ethyl-3(3-dimethylaminopropyl)carbodiimide, 1-hydroxy-1H-benzotriazole) and differences in the conformational behavior of the various peptides were studied. We anticipated that Caas 1 and 2 would define the conformational behavior of b-hGly in 5-12 (Scheme 1).Structural studies on these peptides were carried out by using NMR and CD spectroscopic techniques. The 1 H NMR spectra of 5 and 6 in CDCl 3 show well-resolved backbone proton signals, as well as low-field NH resonances (NH(2)-NH(3) for 5; NH(2)-NH(5) for 6), which indicate the involvement of these NH groups in H bonding. This bonding was further confirmed by solvent titration studies.[12] The coupling constants 3 J CaH/CbH of the peptides (> 10 Hz or < 5 Hz) clearly demonstrate the predominance of a single conformation about the CaÀCb bond (single q valu...