Lipopeptides synthesis

M Tomishima, H Ohki, A Yamada, El Takasugi, K Maki, S Tawara, El Tanaka. FK463, a novel water-soluble echinocandin lipopeptide synthesis and antifungal activity. J Antibiot 52 674-676, 1999. 

Remarkable advances have been made in the synthesis of N- and O-glycosylated amino acids that, in addition to the 5-fattyacyl-cysteine, are the most sensitive derivatives to the conditions of peptide synthesis. The fine tuning of both carbohydrate and peptide chemistry as well as the use of enzymatic methods are required for the synthesis of glycopeptides. " Similarly soft chemistry has to be applied in the case of S-acylated peptides, whereas fat-tyacylation at amino groups raises no additional difficulties.The state of the art in the field of glyco- and lipopeptide synthesis is discussed in details in Vol. E22b, Sections 6.3 and 6.4, respectively. 

In some experiments, the liposomes are supplemented with lipopep-tides that imitate the cytosolic tail of the transmembrane protein p23. Lipopeptide synthesis has been described elsewhere (Bremser et al, 1999 Nickel and Wieland, 2001). The lipopeptide (1 mM in DMSO) is incorporated by a 100-fold dilution in the extruded liposomes suspension (1 mM), giving a surface concentration of 2 mol % (considering the outer leaflet of the liposomes). 

Grunewald, J., Sieber, S.A., Mahlert, C. et al. (2004) Synthesis and derivatization of daptomycin a chemoenzy-matic route to acidic lipopeptide antibiotics. Journal of the American Chemical Society, 126, 17025. 

New insights into the analysis of hydrophobically post-translational modified proteins could be achieved by the construction of lipidated proteins in a combination of bioorganic synthesis of activated lipopeptides and bacterial expression of the protein backbone (Fig. 19). The physico-chemical properties of such artificial lipoproteins differ substantially from those of the corresponding lipopeptides. The pronounced dominance of the hydrophilic protein moiety (e.g., for the Ras protein 181 amino acids) over a short lipopeptide with one or two hydrophobic modifications provides solubility up to 10 4 mol/1, while the biotinylated or fluorescence labeled lipopeptides exhibit low solubility in aqueous solutions and can be applied in the biophysical experiments only in vesicle integrated form or dissolved in organic solvent. 

For instance, in a synthesis of N-Ras lipopeptide 8, the choline ester in the palmitoylated tripeptide 5 was removed selectively and in high yield by means of the butyryl choline esterase (BChE). Efficient cou-... 

Chemoenzymatic Synthesis of Fluorescent N-Ras Lipopeptides and Their Use in Membrane Localization Studies In Vivo, H. Waldmann, M. Schelhaas, E. Nagele, J. Kuhlmann, A. Wittinghofer, H. Schroeder, J. R. Silvius, Angew. Chem. 1997,109, 2334-2337, Angew. Chem. Int. Ed. 1997,36,2238-2241. 

Synthesis of Characteristic Lipopeptides of Lipid Mode-fied Proteins Employing the Allyl Ester as Protecting Group, T. Schmittberger, A. Cotte, H. Waldmann, Chem Commun 1998, 937-940. 

Synthesis of the Palmitoylated and Prenylated C-terminal Lipopeptides of the Human R- and N-Ras Proteins, T. Schmittberger, H. Waldmann, Bioorg. Med. Chem 1999, 7,749-762. 

Roth A, et al. Synthesis of thiol-reactive lipopeptide adjuvants. Incorporation into liposomes and study of their mitogenic effect on mouse splenocytes. Bioconjugate Chem 2004 15 541. 

Synthesis of lipopeptides containing one type of lipid group... 

Caspofungin acetate (9 Cancidas ) E eumocandin Bo Lipopeptide Semi-syntiietic NP Microbial Antifungal Inhibits fungal cell wall synthesis 180-186... 

Aretz W, Meiwes J, Seibert Q Vobis Ci Wink J. (2000) Frinlimicins novel lipopeptide antibiotics with peptidoglycan synthesis inhibiting activity from Actinoplanes Friuliensis sp nov. J Antibiot 53 807-815. 

Naimochelin C (Fig. 15, 54) from the myxobacterium Nannocystis exedens contains two L-Lys and two ( )-cinnamic acid units. The reported mono- and di-methyl esters (nannochelin B and A) may be artifacts from the work-up (198). A synthesis is described (29) (see Sect. 8.4). The ochrobactins (Fig. 15,55) isolated from the sea-shore bacterium Ochrobactrum sp. (214) with the spacer L-lysine are membrane active due to the fatty acid residues (saturated Cg and (2 )-unsaturated Cg and Cio) cf. lipopeptidic siderophores in Sect. 2.8. 

Pharmacology Micafungin is a semisynthetic lipopeptide (echinocandin) synthesized by a chemical modification of a fermentation product of Coleophoma empetri F-11899. Micafungin inhibits the synthesis of 1,3- -D-glucan, an essential component of fungal cell walls, which is not present in mammalian cells. Pharmacokinetics ... 

Mechanism of Action A lipopeptide antibacterial agent that binds to bacterial membranes and causes a rapid depolarization of the membrane potential. The loss of membrane potential leads to inhibition of protein, DNA, and RNA synthesis. Therapeutic Effect Bactericidal. 

---