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Lactam bridge helices

Gabriella Perell, Rachel Staebell, Mehrdad Hairani, Alessandro Cembran, William Charles Krause Pomerantz
Thioethers, sulfoxides, and sulfonium ions, despite diverse physicochemical properties, all engage in non-covalent interactions with proteins. Thioether-containing macrocycles are also attracting attention as protein-protein interaction (PPI) inhibitors. Here we use a model PPI between -helical MLL and KIX to evaluate oxidation effects on sulfur-containing macrocycle structure, stability, and protein affinity. Desolvation effects from varied polarity states were evaluated computationally and experimentally at the side chain, amino acid and peptide level...
June 19, 2017: Chembiochem: a European Journal of Chemical Biology
Marta Ruiz-Santaquiteria, Pedro A Sánchez-Murcia, Miguel A Toro, Héctor de Lucio, Kilian Jesús Gutiérrez, Sonia de Castro, Filipa A C Carneiro, Federico Gago, Antonio Jiménez-Ruiz, María-José Camarasa, Sonsoles Velázquez
A series of 9-mer and 13-mer amide-bridged cyclic peptides derived from the linear prototype Ac-PKIIQSVGIS-Nle-K-Nle-NH2 (Toro et al. ChemBioChem2013) has been designed and synthesized by introduction of the lactam between amino acid side chains that are separated by one helical turn (i, i+4). All of these compounds were tested in vitro as both dimerization and enzyme inhibitors of Leishmania infantum trypanothione reductase (Li-TryR). Three of the 13-mer cyclic peptide derivatives (3, 4 and 6) inhibited the oxidoreductase activity of Li-TryR in the low micromolar range and they also disrupted enzyme dimerization...
April 13, 2017: European Journal of Medicinal Chemistry
Saskia Neukirchen, Viktoria Krieger, Cornelia Roschger, Mario Schubert, Brigitta Elsässer, Chiara Cabrele
Synthetic helical peptides are valuable scaffolds for the development of modulators of protein-protein interactions involving helical motifs. Backbone-to-side chain or side chain-to-side chain constraints have been and still are intensively exploited to stabilize short α-helices. Very often, these constraints have been combined with backbone modifications induced by Cα-tetrasubstituted, β-, or γ-amino acids, which facilitate the α-peptide or α/β/γ-peptide adopting an α-helical conformation. In this work, we investigated the helical character of octapeptides that were cyclized by a Lys-Asp-(i,i + 4)-lactam bridge...
March 29, 2017: Journal of Peptide Science: An Official Publication of the European Peptide Society
Huy N Hoang, Russell W Driver, Renée L Beyer, Timothy A Hill, Aline D de Araujo, Fabien Plisson, Rosemary S Harrison, Lena Goedecke, Nicholas E Shepherd, David P Fairlie
Cyclic pentapeptides (e.g. Ac-(cyclo-1,5)-[KAXAD]-NH2 ; X=Ala, 1; Arg, 2) in water adopt one α-helical turn defined by three hydrogen bonds. NMR structure analysis reveals a slight distortion from α-helicity at the C-terminal aspartate caused by torsional restraints imposed by the K(i)-D(i+4) lactam bridge. To investigate this effect on helix nucleation, the more water-soluble 2 was appended to N-, C-, or both termini of a palindromic peptide ARAARAARA (≤5 % helicity), resulting in 67, 92, or 100 % relative α-helicity, as calculated from CD spectra...
July 11, 2016: Angewandte Chemie
Ji Mao, Takefumi Kuranaga, Hiroshi Hamamoto, Kazuhisa Sekimizu, Masayuki Inoue
A linear peptide, gramicidin A (GA), folds into a β(6.3) -helix, functions as an ion channel in the cell membrane, and exerts antibacterial activity. Herein we describe the rational design, synthesis, and biological evaluation of lactam-bridged GA analogues. The GA analogue with a 27-membered macrolactam was found to adopt a stable β(6.3) -helical conformation and exhibits higher ion-exchange activity than GA. Furthermore, this GA analogue retains the potent antibiotic activity of GA, but its hemolytic activity and toxicity toward mammalian cells are significantly lower than those of GA...
March 2015: ChemMedChem
Mario Scrima, Manuela Grimaldi, Sara Di Marino, Chiara Testa, Paolo Rovero, Anna Maria Papini, Michael Chorev, Anna Maria D'Ursi
The recently introduced Cu(I)-catalyzed azide-alkyne 1,3-dipolar Huisgen cycloaddition as a prototypic "click chemistry reaction" presented an opportunity for introducing the 1,4-disubstituted-[1,2,3]triazolyl moiety as a new isostere for peptide bonds in the backbone. Previous study in our lab focused on the synthesis of a model i-to-i+4 side chain-to-side chain 1,4- and 4,1-disubstituted-[1,2,3]triazolyl-bridged cyclo-nonapeptide I (Scheme 1) as analogues of its structurally related helical i-to-i+4 lactam-bridged cyclo-nonapeptide [Lys¹³ (&¹), Asp¹⁷ (&²)]parathyroid hormone related peptide (PTHrP)(11-19)NH₂ (1) a truncated version of the α-helical and potent parathyroid hormone receptor 1 agonist [Lys¹³ (&¹), Asp¹⁷ (&²)]PTHrP(1-34)NH₂, (2,3) N(α) -Ac-Lys-Gly-Lys(&¹)-Ser-Ile-Gln-Asp(&²)-Leu-Arg-NH₂]...
2012: Biopolymers
Esther Vaz, Sonja A Dames, Matthias Geyer, Luc Brunsveld
Many β-peptides fold in a 14-helical secondary structure in organic solvents, but similar 14-helix formation in water requires additional stabilizing elements. Especially the 14-helix stabilization of short β-peptides in aqueous solution is critical, due to the limited freedom for incorporating stabilizing elements. Here we show how a single lactam bridge, connecting two β-amino acid side-chains, can lead to high 14-helix character in short β(3)-peptides in water. A comparative study, using CD and NMR spectroscopy and structure calculations, revealed the strong 14-helix inducing power of a side-chain-to-side-chain cyclization and its optimal position on the β(3)-peptide scaffold with respect to pH and ionic strength effects...
February 21, 2012: Organic & Biomolecular Chemistry
Keith K Khoo, Michael J Wilson, Brian J Smith, Min-Min Zhang, Joszef Gulyas, Doju Yoshikami, Jean E Rivier, Grzegorz Bulaj, Raymond S Norton
μ-Conotoxin KIIIA (μ-KIIIA) blocks mammalian voltage-gated sodium channels (VGSCs) and is a potent analgesic following systemic administration in mice. Previous structure-activity studies of μ-KIIIA identified a helical pharmacophore for VGSC blockade. This suggested a route for designing truncated analogues of μ-KIIIA by incorporating the key residues into an α-helical scaffold. As (i, i+4) lactam bridges constitute a proven approach for stabilizing α-helices, we designed and synthesized six truncated analogues of μ-KIIIA containing single lactam bridges at various locations...
November 10, 2011: Journal of Medicinal Chemistry
Maoqing Dong, Jerez A Te, Xiequn Xu, Jinhui Wang, Delia I Pinon, Laura Storjohann, Andrew J Bordner, Laurence J Miller
The natural ligands for family B G protein-coupled receptors are moderate-length linear peptides having diffuse pharmacophores. The amino-terminal regions of these ligands are critical for biological activity, with their amino-terminal truncation leading to production of orthosteric antagonists. The carboxyl-terminal regions of these peptides are thought to occupy a ligand-binding cleft within the disulfide-bonded amino-terminal domains of these receptors, with the peptides in amphipathic helical conformations...
September 27, 2011: Biochemistry
N Kondori, L Baltzer, G T Dolphin, I Mattsby-Baltzer
Owing to the increasing number of infections in hospitalised patients caused by resistant strains of fungi, there is a need to develop new therapeutic agents for these infections. Naturally occurring antimicrobial peptides may constitute models for developing such agents. A modified peptide sequence (CFQWKRAMRKVR; HLopt2) based on amino acid residues 20-31 of the N-terminal end of human lactoferrin (hLF) as well as a double-sized human lactoferricin-like peptide (amino acid residues 16-40; HLBD1) were investigated for their antifungal activities in vitro and in vivo...
January 2011: International Journal of Antimicrobial Agents
Andrea Caporale, Mattia Sturlese, Lorenzo Gesiot, Fabrizio Zanta, Angela Wittelsberger, Chiara Cabrele
The N-terminal region of the parathyroid hormone (PTH) is sufficient to activate the G-protein-coupled PTH receptor 1 (PTHR1). The shortest PTH analogue displaying nanomolar potency is the undecapeptide H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH(2) that contains two helix-stabilizing residues (Aib(1,3)). To increase the helical character and proteolytic stability of this linear peptide, we replaced Gln(6,10) with (a) Lys(6) and Glu(10) to introduce a lactam bridge and (b) Ser(6,10) to form a diester bridge upon cross-linking with adipic acid...
November 25, 2010: Journal of Medicinal Chemistry
Eunice N Murage, Guangzu Gao, Alessandro Bisello, Jung-Mo Ahn
Glucagon-like peptide-1 (GLP-1) has the ability to lower the blood glucose level, and its regulatory functions make it an attractive therapeutic agent for the treatment of type 2 diabetes. However, its rapid degradation by enzymes like dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase (NEP) 24.11 severely compromises its effective clinical use. Whereas specific DPP-IV inhibitors have been developed, NEP 24.11 targets multiple sites in the GLP-1 sequence, which makes it difficult to block. To address this drawback, we have designed and synthesized conformationally constrained GLP-1 analogues by introducing multiple lactam bridges that stabilized both alpha-helices in the N- and C-terminal regions simultaneously...
September 9, 2010: Journal of Medicinal Chemistry
Eunice N Murage, Jonathan C Schroeder, Martin Beinborn, Jung-Mo Ahn
To elucidate the receptor-bound conformation of glucagon-like peptide-1 (GLP-1), a series of conformationally constrained GLP-1 analogues were synthesized by introducing lactam bridges between Lys(i) and Glu(i)(+4) to form alpha-helices at various positions. The activity and affinity of these analogues to GLP-1 receptors suggested that the receptor-bound conformation comprises two alpha-helical segments between residues 11-21 and 23-34. It is notable that the N-terminal alpha-helix is extended to Thr(11), and that Gly(22) plays a pivotal role in arranging the two alpha-helices...
December 1, 2008: Bioorganic & Medicinal Chemistry
Esther Vaz, William C Pomerantz, Matthias Geyer, Samuel H Gellman, Luc Brunsveld
Many short beta-peptides adopt well-defined conformations in organic solvents, but specialized stabilizing elements are required for folding to occur in aqueous solution. Several different strategies to stabilize the 14-helical secondary structure in water have been developed, and here we provide a direct comparison of three such strategies. We have synthesized and characterized beta-peptide heptamers in which variously a salt bridge between side chains, a covalent link between side chains, or two cyclically constrained residues have been incorporated to promote 14-helicity...
September 22, 2008: Chembiochem: a European Journal of Chemical Biology
Zhe Yan, Brian Tripet, Robert S Hodges
The Spike (S) protein of SARS-coronavirus (SARS-CoV) mediates viral entry into host cells. It contains two heptad repeat regions, denoted HRN and HRC. We have identified the location of the two interacting HR regions that form the six-helix bundle (B. Tripet, et al, J. Biol. Chem., 279: 20836-20849, 2004). In this study, HRC peptide (1150-1185) was chosen as the region to make structure-based substitutions to design a series of HRC analogs with increased hydrophobicity, helical propensity and electrostatic interactions, or with a covalent constraint (lactam bridge) to stabilize the alpha-helical conformation...
August 2006: Journal of Structural Biology
Marcos A Fázio, Vani X Oliveira, Philippe Bulet, M Terêsa M Miranda, Sirlei Daffre, Antonio Miranda
Gomesin is an antimicrobial peptide isolated from hemocytes of the Brazilian spider Acanthoscurria gomesiana that contains two disulfide bridges Cys(2-15)/Cys(6-11) and presents a beta-hairpin structure. To investigate the role of the disulfide bridges on gomesin conformation, bioactivities, and serum stability, structure-activity relationship (SAR) studies were conducted. Initially, gomesin and variants lacking one or both disulfide bridges were synthesized. CD studies showed that the gomesin structure is very rigid independently of the solvent environment...
2006: Biopolymers
Florence M Brunel, Philip E Dawson
We present a straightforward and high yielding method to synthesize constrained helical peptides via thioether ligation; this method represents an attractive alternative to the formation of lactam bridge constraints to induce helicity in peptides.
May 28, 2005: Chemical Communications: Chem Comm
E Schievano, K Pagano, S Mammi, E Peggion
Aib-rich side-chain lactam-bridged oligomers Ac-(Glu-Aib-Aib-Lys)n-Ala-OH with n = 1,2,3 were designed and synthesized as putative models of the 3(10)-helix. The lactam bridge between the side chains of L-Glu and L-Lys in (i)--(i + 3) positions was introduced in order to enhance the structural preference toward the right-handed 3(10)-helix. The conformational properties of the three peptides were studied in trifluoroethanol (TFE) solution by CD, NMR, and computer simulations. The structural information was derived mainly from the analysis of nuclear Overhauser effect spectroscopy spectra...
2005: Biopolymers
Bin Yang, Dongxiang Liu, Ziwei Huang
Protein-protein interactions within the Bcl-2 family are mediated by the helical BH3 domains of pro-apoptotic family members. To study the mechanism of this BH3 domain-protein interaction, a series of cyclic lactam bridged BH3 peptide analogues were synthesized by a novel combined Fmoc/tBu/Bzl protections strategy. These peptide analogues were studied by circular dichroism spectroscopy and found to adopt highly helical structure. These helical peptides stabilized by a lactam bridge serve as useful models to analyze the structure-function relationship of the pro-apoptotic BH3 domains...
March 22, 2004: Bioorganic & Medicinal Chemistry Letters
Natia Tsomaia, Maria Pellegrini, Kimberly Hyde, Thomas J Gardella, Dale F Mierke
The N-terminal fragment of PTH(1-34) is critical for PTH1 receptor activation. Various modifications of PTH(1-14) have been shown to result in a considerable increase in signaling potency [Shimizu et al. (2000) J. Biol. Chem. 275, 21836-21843]. Our structural investigations revealed an unusually stable helical structure of the signaling domain (1-14), where residues 6 (Gln) and 10 (Gln or Asn) were located on the same face of the alpha-helix. To test whether a stable N-terminal alpha-helix is required for productive interaction with PTH1 receptor, we designed two conformationally restricted PTH(1-14) analogues, each containing a lactam bridge at positions 6 and 10...
January 27, 2004: Biochemistry
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