Daptomycin is an important Ca2+ -dependent cyclic lipodepsipeptide antibiotic used to treat serious gram-positive infections. The search for daptomycin analogs with improved activity and their application as tools for studying its mechanism of action has prompted us to develop an entirely Fmoc solid phase approach to the synthesis of daptomycin analogs. Key to the success of this approach was the development of conditions that allowed for the formation of the ester bond on resin-bound peptides consisting of residues 1-10 and the decanoyl lipid tail. The esterification reaction proceeded more efficiently on Tentagel resin as opposed to standard polystyrene resin. This approach was used to synthesize a series of analogs in which each position of Dap-E12-W13, a relatively active daptomycin analog, was individually substituted by alanine. Only positions 2, 6, and 11 were found to be amenable to substitution by alanine in that the corresponding alanine analogs were only 1.5- to 4-fold less active than Dap-E12-W13. We also found that the daptomycin analog, Dap-K6-E12-W13, exhibits in vitro activity approaching that of daptomycin at physiological Ca2+ concentration. Studies with Dap-K6-E12-W13 and model liposomes indicate that this analog interacts with membranes by the same mechanism as daptomycin. This analog is currently being used as a lead for the development daptomycin analogs with improved activity.

中文翻译：

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一种完全fmoc固相合成达托霉素类似物的方法。

达托霉素是一种重要的Ca2 +依赖性环脂肽肽抗生素，用于治疗严重的革兰氏阳性感染。寻找具有改善的活性的达托霉素类似物及其作为研究其作用机理的工具的应用促使我们开发了完全Fmoc固相方法来合成达托霉素类似物。该方法成功的关键是开发条件，该条件允许在由残基1-10和癸酰基脂质尾巴组成的树脂结合肽上形成酯键。与标准聚苯乙烯树脂相比，在Tentagel树脂上的酯化反应更有效地进行。该方法用于合成一系列类似物，其中相对活跃的达托霉素类似物Dap-E12-W13的每个位置分别被丙氨酸取代。发现仅位置2、6和11可被丙氨酸取代，因为相应的丙氨酸类似物的活性仅比Dap-E12-W13低1.5至4倍。我们还发现达托霉素类似物Dap-K6-E12-W13在生理Ca2 +浓度下具有接近达托霉素的体外活性。对Dap-K6-E12-W13和模型脂质体的研究表明，该类似物通过与达托霉素相同的机理与膜相互作用。该类似物目前被用作开发具有改进活性的达托霉素类似物的先导。在生理上的Ca2 +浓度下具有接近达托霉素的体外活性。对Dap-K6-E12-W13和模型脂质体的研究表明，该类似物通过与达托霉素相同的机理与膜相互作用。该类似物目前被用作开发具有改进活性的达托霉素类似物的先导。在生理上的Ca2 +浓度下具有接近达托霉素的体外活性。对Dap-K6-E12-W13和模型脂质体的研究表明，该类似物通过与达托霉素相同的机理与膜相互作用。该类似物目前被用作开发具有改进活性的达托霉素类似物的先导。