113-73-5Relevant articles and documents
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.
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.
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.
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.
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.
Antimicrobial analogues of gramicidin S
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Page/Page column 29; 33; 34, (2019/07/29)
Disclosed herein are N-aminated variants of Gramicidin S and methods of using the same for treating infections in a subject.
