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The two peptides, rich in C(alpha)-tetrasubstituted amino acids, Ac-[Aib-L-(alphaMe)Val-Aib](2)-L-His-NH(2) (1) and Ac-[Aib-L-(alphaMe)Val-Aib](2)-O-tBu (2 a) are prevalently helical. They present the unique property of changing their conformation from the alpha- to the 3(10)-helix as a function of the polarity of the solvent: alpha in more polar solvents, 3(10) in less polar ones. Conclusive evidence of this reversible change of conformation is reported on the basis of the circular dichroism (CD) spectra and a detailed two-dimensional NMR analysis in two solvents (trifluoroethanol and methanol) refined with molecular dynamics calculations. The X-ray diffractometric analysis of the crystals of both peptides reveals that they assume a prevalent 3(10)-helix conformation in the solid state. This conformation is practically superimposable on that obtained from the NMR analysis of 1 in methanol. The NMR results further validate the reported CD signature of the 3(10)-helix and the use of the CD technique for its assessment.

We synthesized by solution-phase methods three analogues, [L-Leu6-OMe], [L-(αMe)Leu3, L-Leu6-OMe], and [L-(αMe)Val4, L-Leu6-OMe] of halovir A. The [L-Leu6-OMe] analogue is known to be biologically equipotent to its naturally occurring, antiviral, lipopentapeptide amide parent compound. The preferred conformations of the L-(αMe)Leu- and L-(αMe)Val-containing analogues, with a potentially reinforced helicity, were compared with those of [L-Leu6-OMe] halovir A and the natural peptide itself by use of a combination of FT-IR absorption and NMR techniques. Measurements of the antiviral activities against herpes simplex virus type-1 (HSV-1) of halovir A and its three analogues were also carried out. Interestingly, the [L-(αMe)Val4, L-Leu6-OMe] analogue exhibits the most significant activity in reducing HSV-1 infectivity, notably higher than that of halovir A itself. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd.

We describe the X-ray diffraction structure of the terminally protected dipeptide amide Boc-Aib-L-Mag-NHBzl (Aib is alpha-aminoisobutyric acid and Mag is C-alpha-methyl, C-a-allyl-glycine) and the results of conformational energy computations on Ac-L-Mag-NHMe, Ac-Aib-L-Mag-NHMe, and Ac-L-Mag-Aib-NHMe. On the basis of these data, we performed conformational energy computations on the sequence -Aib-Xxx-(Aib)(2)-Xxxx-Aib- (Xxx = L-Mag) to check the feasibility of ring-closing metathesis, a currently extensively investigated reaction useful to enhance peptide helicity and metabolic stability, on this 3(10)-helix forming model hexamer with the two olefinic amino acids at the i, i+3 relative positions. Computations were extended to peptides based on olefinic residues with the side chains elongated by one (L-hMag) or two (L-hhMag) carbon atoms. A comparison was also made with peptides characterized by the related, non-C-alpha-methylated (C-alpha-trisubstituted) L-Agl (C-alpha-allyl-L-glycine), L-hAgl, and L-hhAgl residues. We conclude that, to achieve ring-closing metathesis with an unperturbed 3(10)-helical conformation and a symmetrical all-hydrocarbon tether, the side-chain length for each of the two i, i+3 olefinic amino acids requires at least five carbon atoms (hhMag or hhAgl), thereby producing an 18-atom macrocycle.

A N-(8-mercaptooctanoyl)heptapeptide, comprising six CĄ-tetrasubstituted amino acids and a C-terminal histidine residue, has been synthesized by solution methods. The preferred conformation of this peptide and its hexapeptide precursor is that of a 310-helix. Gold nanoparticles have been functionalized with the peptide-thiol by place exchange reaction and the spectroscopic data indicate that the helical conformation of the peptide is maintained in the aggregate. The material obtained may constitute a synthetic model of a globular protein.

Using a combined chemical/chiral chromatographic approach we synthesized an N-protected derivative of (R)-c(3)Val, a severely conformationally restricted C-alpha-tetrasubstituted alpha-amino acid characterized by a C-beta,C-beta-dimethylated cyclopropane system. A set of terminally protected derivatives and model peptides (to the heptamer level), containing one or two (R)-c(3)Val residues in combination with either Aib or Gly residues, was prepared by solution methods. A detailed solution and crystal-state conformational investigation, based on Fourier transform infrared (FTIR) absorption, H-1-NMR, and x-ray diffraction techniques, performed in comparison with a similar study on related derivatives and peptides rich in (alphaMe)Val, the prototype of C-alpha-tetrasubstituted alpha-amino acids of this subfamily, allowed us to conclude the following: (a) c(3)Val is a good beta-bend and helix former, although less efficient than (alphaMe)Val. (b) The relationship between alpha-carbon chirality and screw sense of the folded structure formed is the same as that of (alphaMe) Val, i.e., the (R)-enantiomer has a strong left-handed bias. (c) c(3)Val seems more prone than (alphaMe)Val to fold into a gamma-bend conformation. The conformational propensities of C-beta,C-beta-disubstituted Ac(3)c residues are also discussed in comparison with those of the parent cyclopropane residue.

The achiral, nitroxyl-contg. a-amino acid TOAC (TOAC = 2,2,6,6- tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid), in combination with the chiral a-amino acid Ca-Me valine [(aMe)Val], was used to prep. short peptides (from di- to hexa-) that induced the enantioselective oxidn. of racemic 1-phenylethanol to acetophenone. The best catalyst was an Na-acylated dipeptide alkylamide with the -TOAC-(aMe)Val- sequence folded in a stable, intramolecularly hydrogen-bonded b-turn conformation with large, lipophilic (hydrophobic) N- and C-terminal blocking groups. We rationalized our findings by proposing models for the diastereomeric intermediates between (R)-[and (S)]-1-phenylethanol and the catalyst Fmoc- TOAC-L-(aMe)Val-NHiPr, based on the X-ray diffraction structure of the latter.

A complete series of Nα-protected, monodispersed homooligopeptide esters to the pentamer level from L-Cα-methyl,Cα-allylglycine (L-Mag) have been synthesized step-by-step in solution and fully characterized. The solution preferred conformation of these homooligomers has been assessed by FT-IR absorption and 1H NMR techniques. Moreover, the molecular structures of the homedimer and trimer have been determined in the crystal state by X-ray diffraction, and the conformational energy map of the homotrimer has been computed. The results obtained point to the conclusion that right-handed, single, or multiple β-bends are preferentially adopted by the conformationally restricted L-Mag homooligomers. In particular, 310-helices are formed by the longest homooligomer (pleionomer). The implications for the use of the Mag residue in designing conformationally constrained peptide substrates for reactions involving the side-chain C=C functionality are briefly discussed.

The crystal-state preferred conformations of six Nα-blocked pentapeptide esters, each containing four helicogenic, achiral α-aminoisobutyric acid (Aib) residues followed by one chiral L-valine (L-Val) or Cα-methyl-L-valine [(αMe)Val] residue at the C-terminus, have been assessed by x-ray diffraction analysis. In all of the compounds the - (Aib)4 - sequence is folded in a regular 310-helical conformation. In the four pentapeptides characterized by the L-(αMe)Val residue two conformationally distinct molecules occur in the asymmetric unit. Conversely, only one molecule is observed in the asymmetric unit of two pentapeptides with the C-terminal L-Val residue. In the L-Val based peptides the helical screw sense of the - (Aib)4 - sequence is right-handed, whereas in the L - (αMe)Val - analogues both right- and left-handed helical screw senses concomitantly occur in the two crystallo graphic ally independent molecules. © 1998 John Wiley & Sons, Inc. Biopoly 46: 433-443, 1998.