cas 113-73-5, GRAMICIDIN C | Articles data

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Rapid, Traceless, AgI-Promoted Macrocyclization of Peptides Possessing an N-Terminal Thioamide
Peptide macrocyclization is often a slow process, plagued by epimerization and cyclodimerization. Herein, we describe a new method for peptide macrocyclization employing the AgI-promoted transformation of peptide thioamides. The AgI has a dual function: chemoselectively activating the thioamide and tethering the N-terminal thioamide to the C-terminal carboxylate. Extrusion of Ag2S generates an isoimide intermediate, which undergoes acyl transfer to generate the native cyclic peptide, resulting in a rapid, traceless macrocylization process. Cyclic peptides are furnished in high yields within 1 hour, free of epimerization and cyclodimerization.
Thombare, Varsha J.,Hutton, Craig A.
p. 4998 - 5002
(2019)
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Design and Discovery of Natural Cyclopeptide Skeleton Based Programmed Death Ligand 1 Inhibitor as Immune Modulator for Cancer Therapy
Blockade of immune checkpoint PD-1/PD-L1 facilitates the rescue of immune escapes of tumor cells. Though various monoclonal antibodies have been approved for clinical therapy, the development of small molecular inhibitors lags behind antibodies partially owing to the challenges of protein-protein interaction (PPI) blocker design. In this work, we adopted the skeleton of natural cyclopeptidic antibiotics gramicidin S as the start point for PD-1/PD-L1 inhibitor exploring and discovered a series of novel cyclopeptides that could interfere with the PPI of PD-1/PD-L1 based on several rounds of structural design and optimization. The representative active cyclopeptide 66 can bind two PD-L1 and efficiently block the PD-1/PD-L1 interaction, recruit the immune cells to the tumor cells, enhance their killing against tumor cells by promoting the release of granzyme B and perforin, and display significant CD8+ T cell-dependent tumor suppression activity in vivo.
Sun, Haixia,Chen, Daoyuan,Zhan, Siyue,Wu, Weijian,Xu, Huiying,Luo, Chunxiang,Su, Hui,Feng, Yanqiao,Shao, Weiyan,Wan, Arabella,Zhou, Binhua,Wan, Guohui,Bu, Xianzhang
p. 11286 - 11301
(2020)
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Development of Therapeutic Gramicidin S Analogues Bearing Plastic β,γ-Diamino Acids
Gramicidin S (GS), one of the most widely investigated antimicrobial peptides (AMPs), is known for its robust antimicrobial activity. However, it is restricted to topical application due to undesired hemolytic activity. With the aim of obtaining nontoxic GS analogues, we describe herein a molecular approach in which the native GS β-turn region is replaced by synthetic β,γ-diamino acids (β,γ-DiAAs). Four β,γ-DiAA diastereomers were employed to mimic the β-turn structure to afford GS analogues GS3–6, which exhibit diminished hemolytic activity. A comparative structural study demonstrates that the (βR,γS)-DiAA is the most-stable β-turn mimic. To further improve the therapeutic index (e. g., high antibacterial activity and low hemolytic activity) and to extend the molecular diversity, GS5 and GS6 were used as structural scaffolds to introduce additional hydrophobic or hydrophilic groups. We show that GS6K, GS6F and GS display comparable antibacterial activity, and GS6K and GS6F have significantly decreased toxicity. Moreover, antibacterial mechanism studies suggest that GS6K kills bacteria mainly through the disruption of the membrane.
Alezra, Valérie,Chen, Kaisen,Chen, Qiang,Cheng, Keguang,Guan, Qinkun,Hu, Chengfei,Hu, Jianguo,Jin, Yi,Miclet, Emeric,Wan, Yang,Zhu, Jibao
(2020)
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Synthesis of Gramicidin S and Its Analogues via an On-Resin Macrolactamization Assisted by a Predisposed Conformation of the Linear Precursors
A simple and efficient preparation of gramicidin S and its analogues is described. It involves solid-phase peptide synthesis and on-resin macrolactamization without side chain protection, affording cyclic products in high yield and high purity. The high specificity of the cyclization reaction was shown to originate in the formation of a pre-organized conformation of the linear biosynthetic precursor of gramicidin S. This facile method will provide convenient access to the analogues of the natural product for functional optimization to counter microbial resistance.
Bu, Xianzhang,Wu, Xiaoming,Ng, Na Lee Joyce,Mak, Chun Kit,Qin, Chuanguang,Guo, Zhihong
p. 2681 - 2685
(2004)
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Spatially close porphyrin pair linked by the cyclic peptide Gramicidin S
Two porphyrins were attached to the cyclic decapeptide Gramicidin S and its analogs via the side chain amide bonds and the solvent-dependent molecular structure was characterized by various spectroscopic methods.
Arai, Toru,Maruo, Naoki,Sumida, Yuko,Korosue, Chie,Nishino, Norikazu
p. 1503 - 1504
(1999)
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Relationship between the cyclization and conformation of pentapeptide active esters related to gramicidin S having no protecting group on the side chain of the ornithine residue
To investigate the contribution of the D-phe-Pro-Val sequence in the direct formation of gramicidin S (GS) by the dimerization-cyclization of pentapeptide-active esters having no protecting group on the side chain of the Orn residue, the cyclization of four H-X-Pro-Y-Orn-Leu-ONSu's (X = L- or D-Phe, Y = L- or D-Val, -ONSu = succinimide ester) was examined. Only H-D-Phe-Pro-Val-Orn-Leu-ONSu gave semi-GS (cyclic monomer) and GS (cyclic dimer) in yields of 15 and 38%, respectively. The active ester with a D-Phe-Pro-D-Val sequence produced exclusively [D-Val]-semi-GS in 58% yield. On the other hand, the active esters having Phe-Pro-Val and Phe-Pro-D-Val sequences did not yield any amount of cyclic monomer and cyclic dimer. The change in the configurations of the Phe and Val residues around the Pro residue greatly affected the CD spectra in ethanol and the 1H NMR spectra in DMSO-d6 of the pentapeptide ethyl esters corresponding to four H-X-Pro-Y-Orn-Leu-ONSu's. A good correlation among the CD spectra, NMR spectra of the pentapeptide ethyl esters, and the main products in the cyclization of the active esters was found.
Tamaki, Makoto,Komiya, Seiji,Akabori, Sadatoshi,Muramatsu, Ichiro
p. 899 - 904
(1997)
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Synthetic Lugdunin Analogues Reveal Essential Structural Motifs for Antimicrobial Action and Proton Translocation Capability
Lugdunin, a novel thiazolidine cyclopeptide, exhibits micromolar activity against methicillin-resistant Staphylococcus aureus (MRSA). For structure–activity relationship (SAR) studies, synthetic analogues obtained from alanine and stereo scanning as well as peptides with modified thiazolidine rings were tested for antimicrobial activity. The thiazolidine ring and the alternating d- and l-amino acid backbone are essential. Notably, the non-natural enantiomer displays equal activity, thus indicating the absence of a chiral target. The antibacterial activity strongly correlates with dissipation of the membrane potential in S. aureus. Lugdunin equalizes pH gradients in artificial membrane vesicles, thereby maintaining membrane integrity, which demonstrates that proton translocation is the mode of action (MoA). The incorporation of extra tryptophan or propargyl moieties further expands the diversity of this class of thiazolidine cyclopeptides.
Schilling, Nadine A.,Berscheid, Anne,Schumacher, Johannes,Saur, Julian S.,Konnerth, Martin C.,Wirtz, Sebastian N.,Beltrán-Bele?a, José M.,Zipperer, Alexander,Krismer, Bernhard,Peschel, Andreas,Kalbacher, Hubert,Br?tz-Oesterhelt, Heike,Steinem, Claudia,Grond, Stephanie
p. 9234 - 9238
(2019)
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Biomimetic synthesis of gramicidin s and analogues by enzymatic cyclization of linear precursors on solid support.
[reaction: see text] Gramicidin S is a potent decapeptide antibiotic with high hemolytic activity but is unlikely to provoke microbial resistance. Here we demonstrate that gramicidin thioesterase (GrsB TE) correctly cyclizes immobilized linear decapeptide precursors into head-to-tail products, indicating its suitability for parallel solid-phase synthesis of gramicidin analogues from linear precursors on solid support. This chemoenzymatic method will enable the optimization of the therapeutic index of the natural product to fight microbial resistance.
Wu, Xiaoming,Bu, Xianzhang,Wong, Ka Man,Yan, Weili,Guo, Zhihong
p. 1749 - 1752
(2003)
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IBTM-containing gramicidin S analogues: Evidence for IBTM as a suitable type II' β-turn mimetic
The 2-amino-3-oxohexahydroindolizino[8,7-b]indole-5-carboxylate system (IBTM) has been proposed as a dipeptide surrogate of type II' β-turns. To evaluate which of the 11bR and 11bS diastereomers of IBTM best reproduces the conformational properties of type II' β-turns, gramicidin S (GS), a cyclic antibiotic peptide that contains two such units, has been chosen as a test compound and the effect of either diastereomer on both conformation and activity of the resulting peptide analogues has been determined. A conventional approach to the cyclic peptide structure based on solution cyclization of a partially protected precursor was only practicable for the (S)IBTM diastereomer. As an alternative, a solid phase mediated cyclization approach has been devised and applied successfully to both gramicidin S and its Lys2,2' analogue, then extended to the (R)-IBTM-containing analogues. NMR conformational analysis has clearly shown that only the (R) diastereomer of IBTM is a suitable mimic of the type II' β-turn conformation typical of GS. Differences in antibacterial activity between the (S)- and (R)-IBTM-containing GS analogues confirm the conformational results.
Andreu, David,Ruiz, Sergi,Carre?o, Cristina,Alsina, Jordi,Albericio, Fernando,Jiménez, María Angeles,De La Figuera, Natalia,Herranz, Rosario,García-López, María Teresa,González-Mu?iz, Rosario
p. 10579 - 10586
(1997)
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Antimicrobial analogues of gramicidin S
Disclosed herein are N-aminated variants of Gramicidin S and methods of using the same for treating infections in a subject.
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Page/Page column 29; 33; 34

(2019/07/29)

Stabilization of Cyclic β-Hairpins by Ugi-Reaction-Derived N-Alkylated Peptides: The Quest for Functionalized β-Turns
A solid-phase approach including on-resin Ugi reactions was developed for the construction of β-hairpins. Various N-alkylated dipeptide fragments proved capable of aligning antiparallel β-sheets in a macrocyclic scaffold, thus serving as β-hairpin templates. Gramicidin S was used as the model β-hairpin to compare the Ugi-derived β-turns with the type-II′ β-turn. The results show that the multicomponent incorporation of such N-alkylated residues allows for the simultaneous stabilization and exo-cyclic functionalization of cyclic β-hairpins.
Ricardo, Manuel G.,Vasco, Aldrin V.,Rivera, Daniel G.,Wessjohann, Ludger A.
supporting information
p. 7307 - 7310
(2019/10/02)

Photopharmacological Control of Cyclic Antimicrobial Peptides
Gramicidin S is a naturally occurring antimicrobial cyclic peptide. Herein, we present a series of cyclic peptides based on gramicidin S that contain an azobenzene photoswitch to reversibly control secondary structure and, hence, antimicrobial activity. 1H NMR spectroscopy and density functional theory calculations revealed a β-sheet/β-turn secondary structure for the cis configuration of each peptide, and an ill-defined conformation for all associated trans structures. The cis-enriched and trans-enriched photostationary states (PSSs) for peptides 1–3 were assayed against Staphylococcus aureus to reveal a clear relationship between well-defined secondary structure, amphiphilicity and optimal antimicrobial activity. Most notably, peptides 2 a and 2 b exhibited a fourfold difference in antimicrobial activity in the cis-enriched PSS over the trans-enriched equivalent. This photopharmacological approach allows antimicrobial activity to be regulated through photochemical control of the azobenzene photoswitch, thereby opening new avenues in the design and synthesis of future antibiotics.
Yeoh, Yuan Qi,Yu, Jingxian,Polyak, Steven W.,Horsley, John R.,Abell, Andrew D.
p. 2591 - 2597
(2018/11/23)

Stabilizing amyloid-β peptide by the N-terminus capture is capable of preventing and eliminating amyloid-β oligomers
Elimination of amyloid-β (Aβ) oligomers remains challenging. We describe here a novel strategy to prevent and eliminate the Aβ oligomers from either the early aggregation or the fibril dissolution pathway by targeting the flexible N-terminus, but not the widely investigated hydrophobic segment, with a rationally designed cyclopeptide.
Wen, Gesi,Chen, Daoyuan,Qin, Wenjing,Zhou, Binhua,Wang, Youqiao,Liu, Ziyi,Du, Jun,Zhou, Qiang,Quan, Junmin,Bu, Xianzhang
supporting information
p. 7673 - 7676
(2017/07/12)

Dissociation of antimicrobial and hemolytic activities of gramicidin S through N-methylation modification
β-Sheet antimicrobial peptides (AMPs) are well recognized as promising candidates for the treatment of multidrug-resistant bacterial infections. To dissociate antimicrobial activity and hemolytic effect of b-sheet AMPs we hypothesize that N-methylation of the intramolecular hydrogen bond(s)-forming amides could improve their specificities for microbial cells over human erythrocytes. We utilized a model b-sheet antimicrobial peptide gramicidin S (GS) to study the N-methylation effects on the antimicrobial and hemolytic activities. We synthesized twelve N-methylated GS analogues by replacement of residues at the β-strand and β-turn regions with N-methyl amino acids and tested their antimicrobial and hemolytic activities. Our experiments showed that the HC50 values increased fivefold compared with that of GS when the internal hydrogen-bonded leucine residue was methylated. Neither hemolytic effect nor antimicrobial activity changed when proline alone was replaced with N-methylalanine in the b-turn region. However analogues containing N-methylleucine at β-strand and N-methylalanine at β-turn regions exhibited a fourfold increase in selectivity index compared to GS. We also examined the conformation of these N-methylated GS analogues using 1H NMR and circular dichroism (CD) spectroscopy in aqueous solution and visualized the backbone structures and residue orientations using molecular dynamics simulations. The results show that N-methylation of the internal hydrogen bond-forming amide affected the conformation backbone shape and side chain orientation of GS.
Li, Yangmei,Bionda, Nina,Yongye, Austin,Geer, Phaedra,Stawikowski, Maciej,Cudic, Predrag,Martinez, Karina,Houghten, Richard A.
p. 1865 - 1872
(2014/01/06)

Chemoselective cyclization of unprotected linear peptides by α-ketoacid-hydroxylamine amide-ligation
Cyclic peptides are important synthetic targets due to their constrained conformation, enhanced metabolic stability and improved bioavailability, which combine to make them promising lead compounds for drug candidates. They are typically synthesized by a multi-step sequence of carefully orchestrated protecting group manipulations and cyclization of side-chain protected linear precursors. In the present manuscript we disclose an alternative approach to the synthesis of peptide macrocycles by the α-ketoacid-hydroxylamine (KAHA) ligation. This reaction allows readily prepared linear peptides to be cyclized without reagents or side-chain protecting groups and delivers a native backbone amide bond at the ligation site. The precursors are prepared with Fmoc-based solid phase peptide synthesis using reagents that we have previously disclosed. No post-cyclization manipulations or deprotections other than purification are required. This protocol was applied to five different cyclic peptide natural products of varying ring sizes and side chain functionalities.
Fukuzumi, Takeo,Ju, Lei,Bode, Jeffrey W.
supporting information; experimental part
p. 5837 - 5844
(2012/08/28)

Solvent-free thermocyclization of the unactivated linear gramicidin S precursor and analogues
A convenient thermocyclization of the linear gramicidin S precursor and its analogues is demonstrated. With the preorganized β-sheet conformation, the unactivated linear precursors can cyclize into the corresponding head-to-tail cyclic products in high yield after being heated under solvent-free conditions.
An, Lin-Kun,Li, Run-Lin,Zuo, Ying-Lin,Gu, Lian-Quan
supporting information; experimental part
p. 34 - 37
(2011/03/22)

Therapeutic index of gramicidin S is strongly modulated by D-phenylalanine analogues at the β-turn
Analogues of the cationic antimicrobial peptide gramicidin S (GS), cyclo(Val-Orn-Leu-D-Phe-Pro)2, with D-Phe residues replaced by different (restricted mobility, mostly) surrogates have been synthesized and used in SAR studies against several p
Solanas, Conceptión,De La Torre, Beatriz G.,Fernández-Reyes, María,Santiveri, Clara M.,Jiménez, M. ángeles,Rivas, Luis,Jiménez, Ana I.,Andreu, David,Cativiela, Carlos
experimental part
p. 664 - 674
(2009/11/30)

Biomimetic formation of gramicidin S by dimerization-cyclization of pentapeptide precursor on solid support
The biomimetic formation of gramicidin S, cyclo(-d-Phe-Pro-Val-Orn-Leu-)2, by the dimerization and cyclization of pentapeptide precursor without the protection of δ-amino group of the Orn residue was examined on a solid support. The cyclization of H-d-Phe-Pro-Val-Orn-Leu-oxime on a resin with an oxime group of 0.62 mmol/g in 1,4-dioxane directly gave gramicidin S in a 50% yield. The dimerization-cyclization mode on the solid support was similar to that of the biosynthesis of gramicidin S on an enzyme.
Tamaki, Makoto,Honda, Kenji,Kikuchi, Sho,Ishii, Rie
p. 8475 - 8478
(2007/10/03)

Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells
A treatment solution used to prevent posterior capsular opacification is applied or introduced into the lens capsular bag before, during, or after cataract surgery. The treatment solution may also be applied to an intraocular lens prior to surgery. The treatment solution comprises an ion transport mechanism interference agent, which either alone or in combination with other treatment agents such as an osmotic stress agent and an agent to establish a suitable pH, selectively induces detachment and/or death of lens epithelial cells such that posterior capsular opacification is prevented. While the ion transport mechanism interference agent is capable of interfering with the cellular mechanisms and cell ion distribution of a broad range of cells, a concentration of agent is selected such that the treatment solution interferes selectively with the cellular mechanisms of lens epithelial cells while leaving other ocular cells substantially unharmed. The treatment solution selectively induces cellular death and/or detachment of lens epithelial cells while other ocular cells and tissue remain substantially unharmed and without lengthy preoperative pre-treatment.
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(2008/06/13)

A practical synthesis of gramicidin S and sugar amino acid containing analogues
A practical gram-scale and high-yielding synthesis of the antimicrobial peptide gramicidin S is presented. An Fmoc-based solid-phase peptide synthesis protocol is employed for the generation of the linear decapeptide precursor, which is cyclized in solution to afford the target compound. The versatility of our method is demonstrated by the construction of eight gramicidin S analogues (15a-h) having nonproteinogenic sugar amino acid residues (4-7) incorporated in the turn regions.
Grotenbreg, Gijsbert M.,Kronemeijer, Martijn,Timmer, Mattie S. M.,El Oualid, Farid,Van Well, Renate M.,Verdoes, Martijn,Spalburg, Emile,Van Hooft, Peter A. V.,De Neeling, Albert J.,Noort, Daan,Van Boom, Jacques H.,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.,Overhand, Mark
p. 7851 - 7859
(2007/10/03)

Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells
A treatment solution used to prevent posterior capsular opacification is applied or introduced into the lens capsular bag before, during, or after cataract surgery. The treatment solution comprises an ion transport mechanism interference agent, which either alone or in combination with other treatment agents such as an osmotic stress agent and an agent to establish a suitable pH, selectively induces detachment and/or death of lens epithelial cells such that posterior capsular opacification is prevented. While the ion transport mechanism interference agent is capable of interfering with the cellular mechanisms and cell ion distribution of a broad range of cells, a concentration of agent is selected such that the treatment solution interferes selectively with the cellular mechanisms of lens epithelial cells while leaving other ocular cells substantially unharmed. The treatment solution selectively induces cellular death and/or detachment of lens epithelial cells while other ocular cells and tissue remain substantially unharmed and without lengthy preoperative pre-treatment.
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(2008/06/13)

Spectroscopic characterization of an assembled pair of free-base and zinc porphyrins linked by the cyclic β-sheet peptide Gramicidin S
A pair of porphyrins was linked to the Orn side chains of Gramicidin S [cyclo(-D-Phe-Pro-Val-Orn-Leu-)2] and its derivatives via the amide bonds; the assorted porphyrins were characterized by various spectroscopic methods. The high-field shifts of the porphyrin signals in the 1H NMR spectrum and the exciton-coupled Cotton effects in the CD spectrum of cyclo[-D-Phe-Pro-Val-Orn(Por)-Leu-]2 are both intense compared to those of cyclo[-D-Phe-Pro-Val-Dab(Por)-Leu-]2 or cyclo[-D-Phe-Pro- Val-Lys(Por)-Leu-]2 (Dab, diaminobutyric acid; Por, the side-chain linked porphyrin). Some 1H NMR signals of the tolyl protons of the porphyrins coalesce at 353 K in CD2Cl2, which reveals dynamic processes of the porphyrins. The intensities of the Cotton effect are: Gramicidin S with a pair of free-base porphyrins ≈ Gramicidin S with a free-base porphyrin and a zinc porphyrin 1H NMR, UV-vis, CD and fluorescence spectra show that the solvent substantially influences the assembly of the porphyrins. These spectroscopic studies suggest that the strength of the intramolecular interactions between a pair of porphyrins is in the order of toluene > CH2Cl2 > DMF.
Arai, Toru,Araki, Koji,Maruo, Naoki,Sumida, Yuko,Korosue, Chie,Fukuma, Kengo,Kato, Tamaki,Nishino, Norikazu
p. 1151 - 1159
(2007/10/03)

Synthesis and biological evaluation of novel turn-modified gramicidin S analogues
The synthesis of novel gramicidin S analogues having additional functionalities in the turn region by employing a biomimetic approach is described. The preservation of β-sheet character in all analogues was established by NMR and the biological activity was evaluated.
Grotenbreg, Gijsbert M.,Spalburg, Emile,De Neeling, Albert J.,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.,Van Boom, Jacques H.,Overhand, Mark
p. 2835 - 2841
(2007/10/03)

Biomimetic synthesis of gramicidin S. Direct formation of the antibiotic from pentapeptide active esters having no protecting group on the side chain of the Orn residue
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Tamaki,Akabori,Muramatsu
p. 10492 - 10496
(2007/10/02)

ONE-POT CYCLIZATION OF A PEPTIDE BY THE USE OF (5-NITROPYRIDYL)DIPHENYL PHOSPHINATE: THE SYNTHESIS OF CYCLIC DECAPEPTIDE GRAMICIDIN S
One-pot synthesis of gramicidin S, cyclic decapeptide, was successfully achieved by treatment of the corresponding linear decapeptide with (5-nitropyridyl)diphenyl phosphinate, a new condensing reagent, in pyridine.Similarly, the phosphinic ester can be successfully employed in the Young test as well as syntheses of dipeptides.
Mukaiyama, Teruaki,Kamekawa, Kenichi,Watanabe, Yutaka
p. 1367 - 1370
(2007/10/02)