![Cyclo[(Val-Orn-(Cbz)-Leu-DPhe-Pro)2]](/Databaselist/images/loading.webp)
113-73-5Relevant academic research and scientific papers
Rapid, Traceless, AgI-Promoted Macrocyclization of Peptides Possessing an N-Terminal Thioamide
Thombare, Varsha J.,Hutton, Craig A.
, p. 4998 - 5002 (2019)
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.
Design and Discovery of Natural Cyclopeptide Skeleton Based Programmed Death Ligand 1 Inhibitor as Immune Modulator for Cancer Therapy
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)
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.
Development of Therapeutic Gramicidin S Analogues Bearing Plastic β,γ-Diamino Acids
Alezra, Valérie,Chen, Kaisen,Chen, Qiang,Cheng, Keguang,Guan, Qinkun,Hu, Chengfei,Hu, Jianguo,Jin, Yi,Miclet, Emeric,Wan, Yang,Zhu, Jibao
, (2020)
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.
Synthesis of Gramicidin S and Its Analogues via an On-Resin Macrolactamization Assisted by a Predisposed Conformation of the Linear Precursors
Bu, Xianzhang,Wu, Xiaoming,Ng, Na Lee Joyce,Mak, Chun Kit,Qin, Chuanguang,Guo, Zhihong
, p. 2681 - 2685 (2004)
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.
Spatially close porphyrin pair linked by the cyclic peptide Gramicidin S
Arai, Toru,Maruo, Naoki,Sumida, Yuko,Korosue, Chie,Nishino, Norikazu
, p. 1503 - 1504 (1999)
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.
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
Tamaki, Makoto,Komiya, Seiji,Akabori, Sadatoshi,Muramatsu, Ichiro
, p. 899 - 904 (1997)
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.
Synthetic Lugdunin Analogues Reveal Essential Structural Motifs for Antimicrobial Action and Proton Translocation Capability
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)
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.
Biomimetic synthesis of gramicidin s and analogues by enzymatic cyclization of linear precursors on solid support.
Wu, Xiaoming,Bu, Xianzhang,Wong, Ka Man,Yan, Weili,Guo, Zhihong
, p. 1749 - 1752 (2003)
[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.
IBTM-containing gramicidin S analogues: Evidence for IBTM as a suitable type II' β-turn mimetic
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)
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.
Stabilization of Cyclic β-Hairpins by Ugi-Reaction-Derived N-Alkylated Peptides: The Quest for Functionalized β-Turns
Ricardo, Manuel G.,Vasco, Aldrin V.,Rivera, Daniel G.,Wessjohann, Ludger A.
supporting information, p. 7307 - 7310 (2019/10/02)
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.
