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The conformational preferences and infrared and ultraviolet spectral signatures of two model [beta]-peptides, [beta]-peptides Ac-[[beta].sup.3]-hPhe-[[beta].sup.3]-hAla-NHMe and Ac-[[beta].sup.3]-hAla-[[beta].sup.3]-hPhe-NHMe, are analyzed under jet-cooled, isolated-molecule conditions. The single conformation spectra has provided characteristic wavenumber ranges for amide NH stretch fundamentals that are attributed to C6, C8 and C10 H-bonded rings.

The conformational preferences and infrared and ultraviolet spectral signatures of two model [beta]-peptides, [beta]-peptides Ac-[[beta].sup.3]-hPhe-NHMe and Ac-[[beta].sup.3]-hTyr-NHMe, are analyzed under jet-cooled, isolated molecule conditions. The characteristic amide NH stretch frequencies for both free amide NH and H-bonded amide NH has served as useful benchmarks for analogous studies of longer [beta]-peptide chains.

The functional host-defense peptide mimics can be created based on a conformational hypothesis that is different from classical helix-induction. The flexible, sequence-random oligomers or polymers containing cationic and lipophilic subunits are induced by a bacterial membrane surface to adopt irregular conformations resulting in global amphiphilicity.

The equilibrium unfolding properties of four model protein systems were characterized using SUPREX (stability of unpurified proteins from rates of H/D exchange). SUPREX is an H/D exchange- and mass spectrometry-based technique for measuring the free energy ([[DELTA]G.sub.f]) and m-value ([[delta][DELTA]G.sub.f]/[delta][denaturant]) associated with the folding/unfolding reaction of a protein. The model proteins in this study (calmodulin, carbonic anhydrase II, RmlB, [Bcl-X.sub.L]) were chosen to test the applicability of SUPREX to the thermodynamic analysis of larger (> ~15 kDa) or multi-domain proteins. In the absence of ligand, [[DELTA]G.sub.f] and m-values for these proteins could not be evaluated using the conventional data acquisition and analysis methods previously established for SUPREX. However, ligand-bound forms of the proteins were amenable to conventional SUPREX analyses, and it was possible to evaluate reasonably accurate and precise binding free energies of selected ligands. In some cases, protein-ligand dissociation constants ([K.sub.d] values) could also be ascertained. The SUPREX-derived binding free energies and [K.sub.d] values evaluated here were in good agreement with those reported on the same complexes using other techniques.

A study presents new information on alpha/beta-peptides that were designed to address questions about the relationships among alpha/beta-amino acid sequence, three-dimensional folding, physical properties, and biological activity. Findings support the conclusion that the global segregation of lipophilic and hydrophilic (cationic) side chains in a helical conformation is not essential for selective antibacterial activity.

The solid-phase synthesis of beta-peptides was optimized using microwave irradiation and this approach was adapted to synthesis on polystyrene macrobeads. A high quality combinatorial library was prepared via a split and mix strategy and this library was screened in search of beta-peptide antagonists of the p53-MDM2 protein-protein interaction.

The structure-activity trends among helix-forming beta-amino acid oligomers that are intended to mimic alpha-helical host-defense peptides are discussed. Results suggest that ampiphilic helical beta-peptides are subject to a comparable limit.

It was examined whether the 12-helix tolerates insertion of acyclic b-amino acid residues bearing a substituent in the alpha-position. The results indicate that a limited number of beta(super 2) residues can be used to introduce side chains at specific positions along the surface of a 12-helix.

The unique structural properties of beta-peptides to determine whether the stability of the biologically active conformation influences antibacterial or hemolytic activity are discussed. Results are relevant to the behavior of alpha-peptides because of mechanistic similarities between these two peptide classes.

A stereoselective synthetic route is reported for the introduction of side chains at the 3-position of trans-2-aminocyclopentanecarboxylic acid (ACPC). ACPC residues allow one to arrange specific functional groups in a geometrically defined fashion, which should facilitate the design of Beta-peptides for biological applications.

Research has been conducted on the antimicrobial agents protegrins. The analogues of these protegrins lacking cysteine but displaying protegrin-like activity have been developed via the use of the beta-hairpin design and the results indicate that antimicrobial potency of the non-disulfide-bonded peptides depends on beta-hairpin conformation stability.

Research demonstrates the antimicrobial activity of the 12-helical beta-peptides. Data indicate a 40% cationic face is optimum for their activity and those with higher cationic face are inactive. The mechanism of action of beta-peptides is similar to those of antimicrobial alpha-peptides and they are impervious to proteases.

Research has been conducted on the polymeric beta-peptides. The authors review the works on the structures of the cyclic peptides containing beta-amino acids.

Research has been conducted on the oligomers of the beta-amino acids. Results indicate that the oligomers composed of the aminocyclopentanecarboxylic acid adopt a helical conformation containing hydrogen bonds between backbone C=O and N-H groups.

A synthesis made of a protected form of (R,R,R,)-2,5-diaminocylohexanecarboxylic acid (DCHC), a monomer, to enable a study of 14-helix formation by short beta-peptides in a water solution is presented. An improved synthesis of protected versions of ACHC itself is also reported.

Research designed to test the hypothesis that parallel hairpin formation can be controlled through the local twist of the linker is presented. It is demonstrated that linkers containing D-proline promote parallel sheet interactions between the strand L-residues.

Issues concerning the NMR spectroscopic examination in solution of the structures of beta-peptides derived from acids are presented. In solution these homooligomers display helixes containing twelve and fourteen membered hydrogen-bonded rings, which are similar to their solid state conformations.

Synthetic protocols and circular dichroism (CD) spectra are presented for a series of oligomers of (R,R)-trans-2-aminocyclopentanecarboxylic acid (trans-ACPC). The two longest oligomers, a hexamer and an octamer, have also been studied crystallographically. Both crystal structures indicated that the beta-peptide backbone adopts a regular helix that is defined by a series of interwoven 12-membered ring hydrogen bonds. Each hydrogen bond links a carbonyl oxygen to an amide proton three residues toward the C-terminus. CD data indicate that the conformational preference of trans-ACPC oligomers in methanol is strongly length-dependent.

Trans-2-aminocyclohexanecarboxylic acid oligomers tend to exhibit a helical conformation under solid state conditions. This helical structure is characterized by 14-membered-ring hydrogen bonds whose residues are situated towards the N terminus and between the carbonyl oxygen and amide proton. Chrystallographic data derived from oligomer samples suggest that the 14-helix structure is a highly stable platform for beta-amino acids.

A study was undertaken to characterize non-peptide inhibitors of leucine zipper formation for the purpose of developing a convenient and sensitive fluorescence assay for homodimerization of a peptide consistent with the leucine zipper region of the Jun oncoprotein. The Jun oncoprotein is a transcription factor that must either homodimerize or create a heterodimer with the Fos oncoprotein to bind to a target DNA site. Results implied that binding of fluorophores can intensely modify leucine zipper behavior.

The hydrogen bond-donating properties of six structurally related secondary amides were probed using N-stretch regio IR spectroscopy. Solid state IR analysis revealed N-H stretch bands greater than 3400 cm-1, indicating the absence of intermolecular N-H--O=C hydrogen bonds. The absence of a standard N-H--O=C interaction was confirmed by crystallographic data.

The third oxidation state of the peptide Ac-YKLAMLEAMAKLMAKLMA-NH2 containing methionine sulfone was studied. The design of the 18-residue peptide, which showed a conformational preference for beta-sheets in water, undergoes redox-induced structure changes in the aggregated states due to the conversion of lipophilic methionine to hydrophilic methionine sulfoxide. This side chain oxidation effect proved the important role played by amphiphilic order in a protein's three-dimensional folding pattern.

A two-step method in which small molecules facilitate protein refolding from a chemically denatured state has been developed. First, the protein is captured by a detergent as guanidinium chloride is diluted to a non-denaturing concentration. Then, a cyclodextrin strips detergent from the protein, permitting the protein to refold. This method was applied to a protein that must form disulfides in the native state. Lysozyme can be refolded from the Gdm-denatured, DTT-reduced state in good yields at final protein concentrations as high as 1 mg/mL with the artificial chaperone method. Various mechanistic aspects of artificial chaperone-assisted refolding were examined and a detailed mechanism for the kinetically controlled stripping step is suggested.

Cylophanes show conformation in which the two aromatic moieties in the macrocycle are intramolecularly oriented in an edge-to-face manner. The maximum upfield shifts in cyclophanes are for aryl protons when an aromatic-aromatic pair is arranged in edge-to face fashion. The lower limit is for molecules containing two aromatic moeities linked more flexibly. Cyclophanes NMR based studies help in the study of more flexible diphenyl and dinaphthyl compounds.

An examination of flexible molecules containing two naphthyl moieties connected by a four atom-linker-bearing carboxyl group identifies minimum increments of hydrophobically induced folding. The four atom linkers allow intramolecular association of the naphthyl groups without much strain in the naphthyl backbone. In dinaphthyl carboxylates, this naphthyl association is detected via upfeild shifts in H NMR signals.

A newly developed synthesis of 1,6-methanol(10)annulene skeleton proceeds through the semi-benzylic Favorskii rearrangement of a (4.4.2)propellane to a (4.4. 1)propellane. This technique offers regiochemically-controlled access to 1, 6-methanol(10)annulene derivatives, which contain substituents on the bridge carbon and annulene ring. Incorporation of annulene substituent by means of adding cuprate to an allylic lactone facilitates the control of substituent positioning.

Studies of the design of unnatural polypeptide backbones that fold in compact and specific patterns reveal that intra-molecular hydrogen bonds between neighboring amide groups in the polypeptide partly controls the folding pattern. Studies of beta-alanine and gamma-amino butyric acid reveal that the former favors hydrogen bonding between neighboring amides. Variable temperature FT-IR studies yield thermodynamic data for hydrogen bond-controlled peptide folding.

Variable-temperature IR spectroscopy is used to study the folding of various depsipeptides, designed from alpha-amino acids (L-proline (P) and L-alanine (A)) and alpha-hydroxy acids (L-lactic acid (L) and glycolic acid (G)), in methylene chloride solution. The sequence context of a specified residue determines the influence of that residue on alpha-helix formation. This is true to the extent that the folding characteristics of these depsipeptides follow the behavior of analogous peptide backbones.

A study was done on the temperature-dependent changes in the folding pattern of a synthetic triamide. Results show that the folding pattern favored at low temperatures in the chlorocarbons contains a single C=O-H-N hydrogen bond in the nine-membered ring while at higher temperatures, a six-membered-ring C=O-H-N is favored. Dimethyl sulfide disrupts all internal hydrogen bonding while acetonitrile destroys the six-membered-ring hydrogen bond.

The behavior of the diamides 3-9 in which eight- or nine-membered hydrogen-bonded rings occur in conformationally restricted frameworks. IR and NMR methods are used to examine the behavior of the new diamides. Results reveal that the use of intramolecular hydrogen-bond formation for the detection of folded states permits the identificaion of frameworks with high propensities to adopt compact conformations.

The synthesis and structural characterization of the four triamides and two esters derived from N-malonylglycine are reported. Three of the triamides exhibit a folded configuration that contains a nine-membered ring N-H...O=C hydrogen bond, indicating that this is the natural conformation of the N-malonylglycine unit. A weak dipolar attraction may also be present within the folded conformations of the said triamides.

A series of amphiphiles with both polar and nonpolar faces in a rigid structure was prepared from a dicarboxylic acid headgroup unit. The rigid headgroup influenced the molecule's tendency towards aggregation. Short flexible nonpolar chains favored noncooperative aggregation while long nonpolar chains underwent cooperative aggregation. Moreover, the structure of the headgroup and tail of the amphiphiles also affected the molecular behavior during aggregation.

Numerous researches are conducted to describe various helix bundle quaternary structures, which are normally formed by oligomers containing several [alpha] and [beta] amino acid residues in aqueous solution, as well as in the crystalline forms. The top-down design approach is found to have wide applications in the development of diverse heterogeneous backbone foldamers by harnessing information embedded in natural [alpha]-amino acid sequences.

The Bcl-X(sub L)/BH3 domain interactions are considered to explore the possibility that unnatural oligomers with discrete folding properties might provide a general basis for development of molecules that block protein-protein interactions. The path from beta-to alpha/beta- to (alpha/beta+alpha)- peptide ligands leads to conclude that foldamer-based strategies for disrupting protein-protein interactions would grow in efficacy as number of foldamer scaffolds with distinct shapes is increased.

Research has been conducted on the trans-3-aminopyrrolidine-4-carboxylic acid. The synthesis of this acid has been carried out and the results are described.

A useful synthesis of (4R,6S)-tetrahydro-2-pyrone derivative in high enantiomeric excess is reported. An immobilized lipase catalyzed selective acylation of (plus over minus))-1-(benzyloxy)-4-penten-2-ol and a ring-closing olefin metathesis with Grubbs' catalyst as the key steps is utilized for this purpose.

The synthesis of phosphine-boranes in a very high state of optical purity is obtained through an excellent method of Pd(0)-Cu(I) cocatalyzed aromatic phosphorylation is shown. The synthesis of new bidentate ligand domains for asymmetric catalysis using this reaction is also reported.

A stereoselective synthesis of (S)-(+)-cocaine, the unnatural enantiomer is reported. The method used can provide access to enantiomerically pure analogues of cocaine and other medicinally significant tropane alkaloids and also be useful in asymmetric synthesis.

The attachment of CoCl2-PPh3 (sub 2) to polymer-supported triphenylphosphine brings about an air-stable versatile immobilized catalyst. A filtration to remove the polymer-supported catalyst in order to isolate the pure product is required as a reaction workup.