1481-70-5

Usage

Purification Methods

Crystallise tyrocidine A as the hydrochloride from MeOH or EtOH/HCl. [Paladin & Craig J Am Chem Soc 76 688 1954, King & Craig J Am Chem Soc 77 6624 1955, Okamoto et al. Bull Chem Soc Jpn 50 231 1977, Beilstein 26 III/IV 4280.]

Upstream product

• 18942-49-9 Boc-D-Phe-OH 
• 71989-31-6 Fmoc-Pro-OH 
• 35661-40-6 N-Fmoc L-Phe 
• 86123-10-6 Fmoc-D-Phe-OH 
• 1139906-59-4 C₁₁₃H₁₃₁N₁₃O₁₅ 
• 72-18-4 L-valine 
• 61-90-5 L-leucine 
• 70-26-8 L-ornithine 
• 70-47-3 L-asparagine 
• 56-85-9 L-glutamine 
• 63-91-2 L-phenylalanine 
• 60-18-4 L-tyrosine 
• 147-85-3 L-proline 
• 1170674-20-0 (2S)-2-amino-3-[4-(prop-2-ynyloxy)phenyl]-propionic acid 

Relevant academic research and scientific papers

SYNTHESIS OF TYROCIDINE A: USE OF OXIME RESIN FOR PEPTIDE CHAIN ASSEMBLY AND CYCLIZATION

Application of the Kaiser oxime resin to the synthesis of the thirty-membered ring cyclo-decapeptide Tyrocidine A (TA) is described.Assembly of the linear peptide chain and its subsequent cyclization with concominant cleavage off the solid support were both achieed in high yield (73.2 and 55percent).

Controlling Antibacterial Activity Exclusively with Visible Light: Introducing a Tetra-ortho-Chloro-Azobenzene Amino Acid

The introduction of a novel tetra-ortho-chloroazobenzene amino acid (CEBA) has enabled photoswitching of the antimicrobial activity of tyrocidine A analogues by using exclusively visible light, granting spatiotemporal control under benign conditions. Compounds bearing this photoswitchable amino acid become active upon irradiation with red light, but quickly turn-off upon exposure to other visible light wavelengths. Critically, sunlight quickly triggers isomerisation of the red light-activated compounds into their original trans form, offering an ideal platform for self-deactivation upon release into the environment. Linear analogues of tyrocidine A were found to provide the best photocontrol of their antimicrobial activity, leading to compounds active against Acinetobacter baumannii upon isomerisation. Exploration of their N- and C-termini has provided insights into key elements of their structure and has allowed obtaining new antimicrobials displaying excellent strain selectivity and photocontrol.

Biosynthetic functionalization of nonribosomal peptides

Nonribosomal peptides (NRPs) are a therapeutically important class of secondary metabolites that are produced by modular synthetases in assembly-line fashion. We previously showed that a single Trp-to-Ser mutation in the initial Phe-loading adenylation domain of tyrocidine synthetase completely switches the specificity toward clickable analogues. Here we report that this minimally invasive strategy enables efficient functionalization of the bioactive NRP on the pathway level. In a reconstituted tyrocidine synthetase, the W227S point mutation permitted selective incorporation of Phe analogues with alkyne, halogen, and benzoyl substituents by the initiation module. The respective W2742S mutation in module 4 similarly permits efficient incorporation of these functionalized substrate analogues at position 4, expanding this strategy to elongation modules. Efficient incorporation of an alkyne handle at position 1 or 4 of tyrocidine A allowed site-selective one-step fluorescent labeling of the corresponding tyrocidine analogues by Cu(I)-catalyzed alkyne-azide cycloaddition. By combining synthetic biology with bioorthogonal chemistry, this approach holds great potential for NRP isolation and molecular target elucidation as well as combinatorial optimization of NRP therapeutics.

Synthesis of tyrocidine A and its analogues by spontaneous cyclization in aqueous solution

(figure presented) Head-to-tail cyclization of peptides is a multistep process involving tedious C-terminal activation and side chain protection. Here we report a facile, quantitative cyclization method in aqueous ammonia solution for the total syntheses of the cyclic decapeptide antibiotic Tyrocidine A and its analogues from their fully deprotected linear thioester precursors on a solid support. This novel aqueous method is conformation-dependent and may be applicable to syntheses of other natural cyclic peptides.

Dissociation of Antibacterial and Hemolytic Activities of an Amphipathic Peptide Antibiotic

Using an alanine-scanning method, we have found that the antibacterial and hemolytic activities of the amphipathic cyclic decapeptide antibiotic tyrocidine A depend on different structural components. Single substitution of glutamine-6 of the natural product with a cationic amino acid results in a therapeutic index enhancement of up to 140-fold. Successful dissociation of the two intimately associated properties should enable discovery of novel analogues with both high bacterial selectivity and antibacterial potency to counter microbial resistance.

Stabilizing the monomeric amyloid-β peptide by tyrocidine A prevents and reverses amyloidogenesis without the accumulation of oligomers

Amyloid-β (Aβ) oligomers are causative agents triggering AD pathogenesis, but their elimination remains challenging. We herein reported a natural cyclopeptide tyrocidine A prevents and reverses amyloidogenesis without Aβ oligomer accumulation by stabilizing the monomeric, but not the oligomeric state of Aβ peptides.

Tyrocidine A Analogues Bearing the Planar d-Phe-2-Abz Turn Motif: How Conformation Impacts Bioactivity

The d-Phe-Pro β-turn of the cyclic β-hairpin antimicrobial decapeptide tyrocidine A, (Tyrc A) was substituted with the d-Phe-2-aminobenzoic acid (2-Abz) motif in a synthetic analogue (1). The NMR structure of 1 demonstrated that compound 1 retained the β-hairpin structure of Tyrc A with additional planarity, resulting in approximately 30-fold reduced hemolysis than Tyrc A. Although antibacterial activity was partially compromised, a single Gln to Lys substitution (2) restored activity equivalent to Tyrc A against S. aureus, enhanced activity against two Gram negative strains and maintained the reduced hemeloysis of 1. Analysis by transmission electron microscopy (TEM) suggested a membrane lytic mechanism of action for these peptides. Compound 2 also exhibits nanomolar antifungal activity in synergy with amphotericin B. The d-Phe-2-Abz turn may serve as a tool for the synthesis of structurally predictable β-hairpin libraries. Unlike traditional β-turn motifs such as d-Pro-Gly, both the 2-Abz and d-Phe rings may be further functionalized.

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.

Synthesis and antibacterial activities of N-Glycosylated derivatives of tyrocidine a, a macrocyclic peptide antibiotic

An efficient and practical method for macrocyclic glycopeptide synthesis was developed and utilized to synthesize tyrocidine A and its glycosylated derivatives. The method is based on solid-phase peptide synthesis using 2-chlorotrityl resin as the solid-phase support and glycosyl amino acids as building blocks. After glycopeptides with fully protected glycans and side chains were released from the acid-labile resin, their Cand N-termini were intramolecularly coupled in solution to afford cyclic glycopeptides in quantitative yields. This synthetic method should be generally applicable to various macrocyclic glycopeptides. Biological studies of the synthetic tyrocidine A derivatives showed that linking glycans directly to the Asn residue of tyrocidine A diminished its antibacterial activity, but linking glycans to Asn via a simple spacer did not. These results Revealed the important impact of glycans on the activities, and probably the structures, of glycopeptide antibiotics.

Solid-phase synthesis and self-assembly formation of tyrocidines

A facile and efficient method was applied for parallel total synthesis of natural cyclic decapeptides, tyrocidine A-E, on safty-catch resin. Synthetic products were equally active as the natural products isolated from the bacterial source and found to possess similar bacterial selectivity as other members in the amphipathic antimicrobial cyclic decapeptide family. At the same time, the self-assembling nanotubes of them were observed under a transmission electronic microscopy.