1481-70-5Relevant articles and documents
SYNTHESIS OF TYROCIDINE A: USE OF OXIME RESIN FOR PEPTIDE CHAIN ASSEMBLY AND CYCLIZATION
Oesapay, George,Profit, Adam,Taylor, John W.
, p. 6121 - 6124 (1990)
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).
Biosynthetic functionalization of nonribosomal peptides
Niquille, David L.,Folger, Ines B.,Basler, Sophie,Hilvert, Donald
, p. 2736 - 2740 (2021)
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.
Dissociation of Antibacterial and Hemolytic Activities of an Amphipathic Peptide Antibiotic
Qin, Chuanguang,Zhong, Xiaofen,Bu, Xianzhang,Ng, Na Lee Joyce,Guo, Zhihong
, p. 4830 - 4833 (2003)
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.
Tyrocidine A Analogues Bearing the Planar d-Phe-2-Abz Turn Motif: How Conformation Impacts Bioactivity
Cameron, Alan J.,Edwards, Patrick J. B.,Harjes, Elena,Sarojini, Vijayalekshmi
, p. 9565 - 9574 (2017/12/26)
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.
