Conformations of helical Aib peptides containing a pair of l‐amino acid and d‐amino acid

A pair of l ‐leucine (l ‐Leu) and d ‐leucine (d ‐Leu) was incorporated into α‐aminoisobutyric acid (Aib) peptide segments. The dominant conformations of four hexapeptides, Boc‐l ‐Leu‐Aib‐Aib‐Aib‐Aib‐l ‐Leu‐OMe (1a), Boc‐d ‐Leu‐Aib‐Aib‐Aib‐Aib‐l ‐Leu‐OMe (1b), Boc‐Aib‐Aib‐l ‐Leu‐l ‐Leu‐Aib‐Aib‐OMe (2a), and Boc‐Aib‐Aib‐d ‐Leu‐l ‐Leu‐Aib‐Aib‐OMe (2b), were investigated by IR, ¹H NMR, CD spectra, and X‐ray crystallographic analysis. All peptides 1a,b and 2a,b formed 3₁₀‐helical structures in solution. X‐ray crystallographic analysis revealed that right‐handed (P) 3₁₀‐helices were present in 1a and 1b and a mixture of right‐handed (P) and left‐handed (M) 3₁₀‐helices was present in 2b in their crystalline states. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.     

Terminal effect of chiral residue on helical screw sense in achiral peptides

To understand the terminal effect of chiral residue for determining a helical screw sense, we adopted five kinds of peptides I – V containing N‐ and/or C‐terminal chiral Leu residue(s): Boc–L ‐Leu–(Aib–ΔPhe)₂–Aib–OMe ( I ), Boc–(Aib–ΔPhe)₂–L ‐Leu–OMe ( II ), Boc–L ‐Leu–(Aib–ΔPhe)₂–L ‐Leu–OMe ( III ), Boc–D ‐Leu–(Aib–ΔPhe)₂–L ‐Leu–OMe ( IV ), and Boc–D ‐Leu–(Aib–ΔPhe)₂–Aib–OMe ( V ). The segment –(Aib–ΔPhe)₂– was used for a backbone composed of two “enantiomeric” (left‐/right‐handed) helices. Actually, this could be confirmed by ¹H‐nmr [nuclear Overhauser effect (NOE) and solvent accessibility of NH resonances] and CD spectroscopy on Boc–(Aib–ΔPhe)₂–Aib–OMe, which took a left‐/right‐handed 3₁₀‐helix. Peptides I – V were also found to take 3₁₀‐type helical conformations in CDCl₃, from difference NOE measurement and solvent accessibility of NH resonances. Chloroform, acetonitrile, methanol, and tetrahydrofuran were used for CD measurement. The CD spectra of peptides I – III in all solvents showed marked exciton couplets with a positive peak at longer wavelengths, indicating that their main chains prefer a left‐handed screw sense over a right‐handed one. Peptide V in all solvents showed exciton couplets with a negative peak at longer wavelengths, indicating it prefers a right‐handed screw sense. Peptide IV in chloroform showed a nonsplit type CD pattern having only a small negative signal around 280 nm, meaning that left‐ and right‐handed helices should exist with almost the same content. In the other solvents, peptide IV showed exciton couplets with a negative peak at longer wavelengths, corresponding to a right‐handed screw sense. From conformational energy calculation and the above ¹H‐nmr studies, an N‐ or C‐terminal L ‐Leu residue in the lowest energy left‐handed 3₁₀‐helical conformation was found to take an irregular conformation that deviates from a left‐handed helix. The positional effect of the L ‐residue on helical screw sense was discussed based on CD data of peptides I – V and of Boc–(L ‐Leu–ΔPhe)_n–L ‐Leu–OMe (n = 2 and 3). © 1999 John Wiley & Sons, Inc. Biopoly 49: 551–564, 1999     

Controlling the helical screw sense of peptides with C‐terminal L‐valine

One chiral L ‐valine (L ‐Val) was inserted into the C‐terminal position of achiral peptide segments constructed from α‐aminoisobutyric acid (Aib) and α,β‐dehydrophenylalanine (Δ^ZPhe) residues. The IR, ¹H NMR and CD spectra indicated that the dominant conformations of the pentapeptide Boc‐Aib‐ΔPhe‐(Aib)₂‐L ‐Val‐NH‐Bn (3) and the hexapeptide Boc‐Aib‐ΔPhe‐(Aib)₃‐L ‐Val‐NH‐Bn (4) in solution were both right‐handed (P) 3₁₀‐helical structures. X‐ray crystallographic analyses of 3 and 4 revealed that only a right‐handed (P) 3₁₀‐helical structure was present in their crystalline states. The conformation of 4 was also studied by molecular‐mechanics calculations. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Ribbon structure stabilized by C10 and C12 turns in αγ hybrid peptide

The present study describes the synthesis and crystallographic analysis of αγ hybrid peptides, Boc‐Gpn‐L‐Pro‐NHMe ( 1 ), Boc‐Aib‐Gpn‐L‐Pro‐NHMe ( 2 ), and Boc‐L‐Pro‐Aib‐Gpn‐L‐Pro‐NHMe ( 3 ). Peptides 1 and 2 adopt expanded 12‐membered (C₁₂) helical turn over γα segment. Peptide 3 promotes the ribbon structure stabilized by type II β‐turn (C₁₀) followed by the expanded C₁₂ helical γα turn. Both right‐handed and left‐handed helical conformations for Aib residue are observed in peptides 2 and 3 , respectively Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.     

Stereochemistry of Schellman motifs in peptides: Crystal structure of a hexapeptide with a C‐terminus 6 → 1 hydrogen bond

The Schellman motif is a widely observed helix terminating structural motif in proteins, which is generated when the C‐terminus residue adopts a left‐handed helical (α_L) conformation. The resulting hydrogen‐bonding pattern involves the formation of an intramolecular 6 → 1 interaction. This helix terminating motif is readily mimicked in synthetic helical peptides by placing an achiral residue at the penultimate position of the sequence. Thus far, the Schellman motif has been characterized crystallographically only in peptide helices of length 7 residues or greater. The structure of the hexapeptide Boc–Pro–Aib–Gly–Leu–Aib–Leu–OMe in crystals reveal a short helical stretch terminated by a Schellman motif, with the formation of 6 → 1 C‐terminus hydrogen bond. The crystals are in the space group P2₁2₁2₁ with a = 18.155(3) Å, b = 18.864(8) Å, c = 11.834(4) Å, and Z = 4 . The final R₁ and wR₂ values are 7.68 and 14.6%, respectively , for 1524 observed reflections [F_o ≥ 3ς(F_o)]. A 6 → 1 hydrogen bond between Pro(1)CO · · · Leu(6)NH and a 5 → 2 hydrogen bond between Aib(2)CO · · · Aib(5)NH are observed. An analysis of the available oligopeptides having an achiral Aib residue at the penultimate position suggests that chain length and sequence effects may be the other determining factors in formation of Schellman motifs. © 1999 John Wiley & Sons, Inc. Biopoly 50: 13–22, 1999     

Solution conformation of a tetradecapeptide stabilized by two di‐n‐propyl glycine residues

The solution conformation of a designed tetradecapeptide Boc‐Val‐Ala‐Leu‐Dpg‐Val‐Ala‐Leu‐Val‐Ala‐Leu‐Dpg‐Val‐Ala‐Leu‐OMe (Dpg‐14) containing two di‐n‐propyl glycine (Dpg) residues has been investigated by ¹H NMR and circular dichroism in organic solvents. The peptide aggregates formed at a concentration of 3 mM in the apolar solvent CDCl₃ were broken by the addition of 12% v/v of the more polar solvent DMSO‐d₆. Successive N_iH N_i+1H NOEs observed over the entire length of the sequence in this solvent mixture together with the observation of several characteristic medium‐range NOEs support a major population of continuous helical conformations for Dpg‐14. Majority of the observed coupling constants ( ) also support ? values in the helical conformation. Circular dichroism spectra recorded in methanol and propan‐2‐ol give further support in favor of helical conformation for Dpg‐14 and the stability of the helix at higher temperature. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Characterization of (Boc‐Cys/Sec‐NHMe)2 and (Boc‐Cys/Sec‐OMe)2: Evidence of local conformational difference between disulfide and diselenide

Conformations of disulfide and diselenide were compared in (Boc‐Cys/Sec‐NHMe)₂ and (Boc‐Cys/Sec‐OMe)₂ using X‐ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, density functional theory (DFT), and circular dichroism (CD) spectroscopy. Conformations of disulfide/diselenide in polypeptides are defined based on the sign of side chain torsion angle χ₃ (–CH₂–S/Se–S/Se–CH₂–); negative indicates left‐handed and positive indicates right‐handed orientation. In the crystals of (Boc‐Cys‐OMe)₂ and (Boc‐Sec‐OMe)₂, the disulfide exhibits a left‐handed and the diselenide a right‐handed orientation. Characterization of cystine and selenocystine derivatives in solution using ¹H‐NMR, natural abundant ⁷⁷Se NMR, 2D‐ROESY, and chemical shift analysis coupled to DMSO titration has indicated the symmetrical nature and antiparallel orientation of Cys/Sec residues about the disulfide/diselenide bridges. Structural calculations of cystine and selenocystine derivatives using DFT further support the antiparallel orientation of Cys/Sec residues about disulfide/diselenide. The far‐ultraviolet (UV) region CD spectra of cystine and selenocystine derivatives have exhibited the negative Cotton effect (CE) for disulfide and positive for diselenide confirming the difference in the conformational preference of disulfide and diselenide. In the previously reported polymorphic structure of (Boc‐Sec‐OMe)₂, the diselenide has right‐handed orientation. In the X‐ray structures of disulfide and diselenide analogues of Escherichia coli protein encoded by curli specific gene C (CgsC) retrieved from Protein Databank (PDB), disulfide has left‐handed and the diselenide right‐handed orientation. The current report provides the evidence for the local conformational difference between a disulfide and a diselenide group under unconstrained conditions, which may be useful for the rational replacement of disulfide by diselenide in polypeptide chains.     

Synthesis and biological evaluation of new active For‐Met‐Leu‐Phe‐OMe analogues containing para‐substituted Phe residues

In the present study, we report synthesis and biological evaluation of the N‐Boc‐protected tripeptides 4a–l and N‐For protected tripeptides 5a–l as new For‐Met‐Leu‐Phe‐OMe (fMLF‐OMe) analogues. All the new ligands are characterized by the C‐terminal Phe residue variously substituted at position 4 of the aromatic ring. The agonism of 5a–l and the antagonism of 4a–l (chemotaxis, superoxide anion production, lysozyme release as well as receptor binding affinity) have been examined on human neutrophils. No synthesized compounds has higher activity than the standard fMLF‐OMe tripeptide to stimulate chemotaxis, although compounds 5a and 5c with ‐CH₃ and ‐C(CH₃)₃, respectively, in position 4 on the aromatic ring, are better than the standard tripeptide to stimulate the production of superoxide anion, in higher concentration. Compounds 4f and 4i , containing ‐F and ‐I in position 4, respectively, on the aromatic ring of phenylalanine, exhibit significant chemotactic antagonism. The influence of the different substitution at the position 4 on the aromatic ring of phenylalanine is discussed. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.     

Conformations of peptides containing a chiral cyclic α, α‐disubstituted α‐amino acid within the sequence of Aib residues

A single chiral cyclic α,α‐disubstituted amino acid, (3S,4S)‐1‐amino‐(3,4‐dimethoxy)cyclopentanecarboxylic acid [(S,S)‐Ac₅c^dOM], was placed at the N‐terminal or C‐terminal positions of achiral α‐aminoisobutyric acid (Aib) peptide segments. The IR and ¹H NMR spectra indicated that the dominant conformations of two peptides Cbz‐[(S,S)‐Ac₅c^dOM]‐(Aib)₄‐OEt ( 1) and Cbz‐(Aib)₄‐[(S,S)‐Ac₅c^dOM]‐OMe (2) in solution were helical structures. X‐ray crystallographic analysis of 1 and 2 revealed that a left‐handed (M) 3₁₀‐helical structure was present in 1 and that a right‐handed (P) 3₁₀‐helical structure was present in 2 in their crystalline states. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Synthesis,conformational study,and spectroscopic characterization of the cyclic Cα,α‐disubstituted glycine 9‐amino‐9‐fluorenecarboxylic acid

A series of terminally blocked peptides (to the pentamer level) from l ‐Ala and the cyclic C^α,α‐disubstituted Gly residue Afc and one Gly/Afc dipeptide have been synthesized by solution method and fully characterized. The molecular structure of the amino acid derivative Boc‐Afc‐OMe and the dipeptide Boc‐Afc‐Gly‐OMe were determined in the crystal state by X‐ray diffraction. In addition, the preferred conformation of all of the model peptides was assessed in deuterochloroform solution by FT‐IR absorption and ¹H‐NMR. The experimental data favour the conclusion that the Afc residue tends to adopt either the fully‐extended (C₅) or a folded/helical structure. In particular, the former conformation is highly populated in solution and is also that found in the crystal state in the two compounds investigated. A comparison with the structural propensities of the strictly related C^α,α‐disubstituted Gly residues Ac₅c and Dϕg is made and the implications for the use of the Afc residue in conformationally constrained analogues of bioactive peptides are briefly examined. A spectroscopic (UV absorption, fluorescence, CD) characterization of this novel aromatic C^α,α‐disubstituted Gly residue is also reported. Copyright © 1999 European Peptide Society and John Wiley & Sons, Ltd.     

The crystal structure of Z‐(Aib)10‐OH at 0.65 Å resolution: three complete turns of 310‐helix

The synthetic peptide Z‐(Aib)₁₀‐OH was crystallized from hot methanol by slow evaporation. The crystal used for data collection reflected synchrotron radiation to sub‐atomic resolution, where the bonding electron density becomes visible between the non‐hydrogen atoms. Crystals belong to the centrosymmetric space group P . Both molecules in the asymmetric unit form regular 3₁₀‐helices. All residues in each molecule possess the same handedness, which is in contrast to all other crystal structure determined to date of longer Aib‐homopeptides. These other peptides are C‐terminal protected by OtBu or OMe. In these cases, because of the missing ability of the C‐terminal protection group to form a hydrogen bond to the residue i‐3, the sense of the helix is reversed in the last residue. Here, the C‐terminal OH‐groups form hydrogen bonds to the residues i‐3, in part mediated by water molecules. This makes Z‐(Aib)₁₀‐OH an Aib‐homopeptide with three complete 3₁₀‐helical turns in spite of the shorter length it has compared with Z‐(Aib)₁₁‐OtBu, the only homopeptide to date with three complete turns.     

Conformational preferences of a short Aib/Ala‐based water‐soluble peptide as a function of temperature

The amino acid Aib predisposes a peptide to be helical with context‐dependent preference for either 3₁₀‐ or α‐ or a mixed helical conformation. Short peptides also show an inherent tendency to be unfolded. To characterize helical and unfolded states adopted by water‐soluble Aib‐containing peptides, the conformational preference of Ac‐Ala‐Aib‐Ala‐Lys‐Ala‐Aib‐Lys‐Ala‐Lys‐Ala‐Aib‐Tyr‐NH₂ was determined by CD, NMR and MD simulations as a function of temperature. Temperature‐dependent CD data indicated the contribution of two major components, each an admixture of helical and extended/polyproline II structures. Both right‐ and left‐handed helical conformations were detected from deconvolution of CD data and ¹³C NMR experiments. The presence of a helical backbone, more pronounced at the N‐terminal, and a temperature‐induced shift in α‐helix/3₁₀‐helix equilibrium, more pronounced at the C‐terminal, emerged from NMR data. Starting from polyproline II, the N‐terminal of the peptide folded into a helical backbone in MD simulations within 5 ns at 60°C. Longer simulations showed a mixed‐helical backbone to be stable over the entire peptide at 5°C while at 60°C the mixed‐helix was either stable at the N‐terminus or occurred in short stretches through out the peptide, along with a significant population of polyproline II. Our results point towards conformational heterogeneity of water‐soluble Aib‐based peptide helices and the associated subtleties. The problem of analyzing CD and NMR data of both left‐ and right‐handed helices are discussed, especially the validity of the ellipticity ratio [θ]₂₂₂/[θ]₂₀₇, as a reporter of α‐/3₁₀‐ population ratio, in right‐ and left‐handed helical mixtures. Proteins 2009. © 2008 Wiley‐Liss, Inc.     

Studies of Amyloid‐Like Fibrillogenesis through β‐Sheet‐Mediated Self‐Assembly of Short Synthetic Peptides

Three structurally different types of small peptides, namely, i) Boc‐Ile‐Aib‐Ile‐OMe (Aib=α‐aminoisobutyric acid), ii) Boc‐Xx‐m‐aminobenzoic acid (Xx=β‐Ala and γ‐aminobutyric acid), and iii) Boc‐Xx‐m‐nitroaniline, were found to exhibit β‐sheet‐mediated fibrillogenesis in the solid state, revealed by FT‐IR, single‐crystal X‐ray diffraction, and FE‐SEM studies. Interestingly, the fibrils grown from peptides 2 and 3 were found to bind with the physiological dye Congo red, a characteristic feature of amyloid fibrils.     

Novel renin inhibitors containing derivatives of N‐alkylleucyl‐β‐hydroxy‐γ‐amino acids

In search for new drugs lowering arterial blood pressure, which could be applied in anti‐hypertensive therapy, research concerning agents blocking of renin‐angiotensin‐aldosteron system has been conducted. Despite many years of research conducted at many research centers around the world, aliskiren is the only one renin inhibitor, which is used up to now. Four novel potential renin inhibitors, having structure based on the peptide fragment 8–13 of human angiotensinogen, a natural substrate for renin, were designed and synthesized. All these inhibitors contain unnatural moieties that are derivatives of N‐methylleucyl‐β‐hydroxy‐γ‐amino acids at the P₂‐P₁' position: 4‐[N‐(N‐methylleucyl)‐amino]‐3‐hydroxy‐7‐(3‐nitroguanidino)‐heptanoic acid (AHGHA), 4‐[N‐(N‐methylleucyl)‐amino]‐3‐hydroxy‐5‐phenyl‐pentanoic acid (AHPPA) or 4‐[N‐(N‐methylleucyl)‐amino]‐8‐benzyloxycarbonylamino‐3‐hydroxyoctanoic acid (AAHOA). The previously listed synthetic β‐hydroxy‐γ‐amino acids constitute pseudodipeptidic units that correspond to the P₁‐P₁' position of the inhibitor molecule. An unnatural amino acid, 4‐methoxyphenylalanin (Phe(4‐OMe)), was introduced at the P₃ position of the obtained compounds. Three of these compounds contain isoamylamide of 6‐aminohexanoic acid (ε‐Ahx‐Iaa) at the P₂'‐P₃' position. The proposed modifications of the selected human angiotensinogen fragment are intended to increase bioactivity, bioavailability, and stability of the inhibitor molecule in body fluids and tissues. The inhibitor Boc‐Phe(4‐OMe)‐MeLeu‐AHGHA‐OEt was obtained in the form of an ethyl ester. The hydrophobicity coefficient, expressed as log P varied between 3.95 and 8.17. In vitro renin inhibitory activity of all obtained compounds was contained within the range 10^?6‐10^?9 M. The compound Boc‐Phe(4‐OMe)‐MeLeu‐AHPPA‐Ahx‐Iaa proved to be the most active (IC₅₀ = 1.05 × 10^?9 M). The compounds Boc‐Phe(4‐OMe)‐MeLeu‐AHGHA‐Ahx‐Iaa and Boc‐Phe(4‐OMe)‐MeLeu‐AHPPA‐Ahx‐Iaa are resistant to chymotrypsin. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.     

Investigation of α/γ hybrid peptide self‐assembled structures with antimicrobial and antibiofilm properties

The present work describes the synthesis and characterization of α/γ hybrid peptides, Boc‐Phe‐γ⁴‐Phe‐Val‐OMe, P1 ; Boc‐Ala‐γ⁴‐Phe‐Val‐OMe, P2 ; and Boc‐Leu‐γ⁴‐Phe‐Val‐OMe, P3 together with the formation of self‐assembled structures formed by these hybrid peptides in dimethyl sulfoxide (DMSO)/water (1:1). The self‐assembled structures were characterized by infrared (IR) spectroscopy, circular dichroism (CD), and scanning electron microscopy (SEM). Further, α/γ hybrid peptide self‐assembled structures were evaluated for antibacterial properties. Among all, the self‐assembled peptide P1 exhibited the antimicrobial activity against Escherichia coli and Klebsiella pneumoniae, while self‐assembled peptide P3 inhibited the biofilms of Salmonella typhimurium and Pseudomonas aeruginosa. In this study, we have shown the significance of self‐assembled structures formed from completely hydrophobic α/γ hybrid peptides in exploring the antibacterial properties together with biofilm inhibition.     

Garcimultiflorone G,a Novel Benzoylphloroglucinol Derivative from Garcinia multiflora with Inhibitory Activity on Neutrophil Pro‐Inflammatory Responses

A novel benzoylphloroglucinol derivative, garcimultiflorone G ( 1 ), was isolated from the fruits of Garcinia multiflora. The structure of 1 was determined through extensive 1D‐ and 2D‐NMR, and MS analyses. Garcimultiflorone G ( 1 ) showed inhibitory effects against superoxide anion (O$\rm{{_{2}^{{^\cdot} -}}}$ ) generation and elastase release by human neutrophils in response to formyl‐L ‐methionyl‐L ‐leucyl‐L ‐phenylalanine/cytochalasin B (fMLP/CB), with IC₅₀ values of 6.97±1.56 and 11.70±1.58 μM , respectively.     

Self‐assembly of short peptides composed of only aliphatic amino acids and a combination of aromatic and aliphatic amino acids

The morphology of structures formed by the self‐assembly of short N‐terminal t‐butyloxycarbonyl (Boc) and C‐terminal methyl ester (OMe) protected and Boc‐deprotected hydrophobic peptide esters was investigated. We have observed that Boc‐protected peptide esters composed of either only aliphatic hydrophobic amino acids or aliphatic hydrophobic amino acids in combination with aromatic amino acids, formed highly organized structures, when dried from methanol solutions. Transmission and scanning electron microscopic images of the peptides Boc‐Ile‐Ile‐OMe, Boc‐Phe‐Phe‐Phe‐Ile‐Ile‐OMe and Boc‐Trp‐Ile‐Ile‐OMe showed nanotubular structures. Removal of the Boc group resulted in disruption of the ability to form tubular structures though spherical aggregates were formed. Both Boc‐Leu‐Ile‐Ile‐OMe and H‐Leu‐Ile‐Ile‐OMe formed only spherical nanostructures. Dynamic light scattering studies showed that aggregates of varying dimensions were present in solution suggesting that self‐assembly into ordered structures is facilitated by aggregation in solution. Fourier transform infrared spectroscopy and circular dichroism spectroscopy data show that although all four of the protected peptides adopt well‐defined tertiary structures, upon removal of the Boc group, only H‐Phe‐Phe‐Phe‐Ile‐Ile‐OMe had the ability to adopt β‐structure. Our results indicate that hydrophobic interaction is a very important determinant for self‐assembly and presence of charged and aromatic amino acids in a peptide is not necessary for self‐assembly. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.     

The crystal structure of Z‐Gly‐Aib‐Gly‐Aib‐OtBu

The synthetic peptide Z‐Gly‐Aib‐Gly‐Aib‐OtBu was dissolved in methanol and crystallized in a mixture of ethyl acetate and petroleum ether. The crystals belong to the centrosymmetric space group P4/n that is observed less than 0.3% in the Cambridge Structural Database. The first Gly residue assumes a semi‐extended conformation (φ ±62°, ψ ?131°). The right‐handed peptide folds in two consecutive β‐turns of type II' and type I or an incipient 3₁₀‐helix, and the left‐handed counterpart folds accordingly in the opposite configuration. In the crystal lattice, one molecule is linked to four neighbors in the ab‐plane via hydrogen bonds. These bonds form a continuous network of left‐ and right‐handed molecules. The successive ab‐planes stack via apolar contacts in the c‐direction. An ethyl acetate molecule is situated on and close to the fourfold axis. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.     

Influence of Mannosylation on Immunostimulating Activity of Adamant‐1‐yl Tripeptide

The mannosylated derivative of adamant‐1‐yl tripeptide (D ‐(Ad‐1‐yl)Gly‐L ‐Ala‐D ‐isoGln) was prepared to study the effects of mannosylation on adjuvant (immunostimulating) activity. Mannosylated adamant‐1‐yl tripeptide (Man‐OCH₂CH(Me)CO‐D ‐(Ad‐1‐yl)Gly‐L ‐Ala‐D ‐isoGln) is a non‐pyrogenic, H₂O‐soluble, and non‐toxic compound. Adjuvant activity of mannosylated adamantyl tripeptide was tested in the mouse model with ovalbumin as an antigen and in comparison to the parent tripeptide and peptidoglycan monomer (PGM, β‐D ‐GlcNAc‐(1→4)‐D ‐MurNAc‐L ‐Ala‐D ‐isoGln‐mesoDAP(εNH₂)‐D ‐Ala‐D ‐Ala), a well‐known effective adjuvant. The mannosylation of adamantyl tripeptide caused the amplification of its immunostimulating activity in such a way that it was comparable to that of PGM.     

Crystallographic characterization of the α,γ C12 helix in hybrid peptide sequences

The solid‐state conformations of two αγ hybrid peptides Boc‐[Aib‐γ⁴(R)Ile]₄‐OMe 1 and Boc‐[Aib‐γ⁴(R)Ile]₅‐OMe 2 are described. Peptides 1 and 2 adopt C₁₂‐helical conformations in crystals. The structure of octapeptide 1 is stabilized by six intramolecular 4 → 1 hydrogen bonds, forming 12 atom C₁₂ motifs. The structure of peptide 2 reveals the formation of eight successive C₁₂ hydrogen‐bonded turns. Average backbone dihedral angles for αγ C₁₂ helices are peptide 1 , Aib; φ (°) = ?57.2 ± 0.8, ψ (°) = ?44.5 ± 4.7; γ⁴(R)Ile; φ (°) = ?127.3 ± 7.3, θ₁ (°) = 58.5 ± 12.1, θ₂ (°) = 67.6 ± 10.1, ψ (°) = ?126.2 ± 16.1; peptide 2 , Aib; φ (°) = ?58.8 ± 5.1, ψ (°) = ?40.3 ± 5.5; ψ⁴(R)Ile; φ (°) = ?123.9 ± 2.7, θ₁ (°) = 53.3 θ 4.9, θ ₂ (°) = 61.2 ± 1.6, ψ (°) = ?121.8 ± 5.1. The tendency of γ⁴‐substituted residues to adopt gauche–gauche conformations about the C^α–C^β and C^β–C^γ bonds facilitates helical folding. The αγ C₁₂ helix is a backbone expanded analog of α peptide 3₁₀ helix. The hydrogen bond parameters for α peptide 3₁₀ and α‐helices are compared with those for αγ hybrid C₁₂ helix. Copyright © 2016 European Peptide Society and John Wiley & Sons.