Synthesis and characterization of the arylomycin lipoglycopeptide antibiotics and the crystallographic analysis of their complex with signal peptidase.
Synthesis and characterization of the arylomycin lipoglycopeptide antibiotics and the crystallographic analysis of their complex with signal peptidase.
复制标题
芳香霉素脂肪肽抗生素的合成和表征以及与信号肽酶进行复合物的晶体学分析。
DOI：
10.1021/ja207318n
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发表时间：
2011-11-09
影响因子：
15
通讯作者：
Romesberg, Floyd E.
中科院分区：
文献类型：
--
作者：
Liu, Jian;Luo, Chuanyun;Smith, Peter A.;Chin, Jodie K.;Page, Malcolm G. P.;Paetzel, Mark;Romesberg, Floyd E.
天然产物的糖基化，包括抗生素，通常在确定它们的物理性质和生物活性方面发挥着重要作用，从而决定它们作为候选药物的潜力。芳霉素类抗生素抑制细菌I型信号肽酶，由三个相关的天然产物组成，其脂肽尾巴连接到一个核心大环上。在此之前，我们报道了几个具有未修饰核心大环的A系列衍生物以及具有硝化大环的B系列衍生物的全合成。我们现在报道了脂糖肽芳香霉素变体的合成和生物学评价，其大环被脱氧-α-甘露糖取代基糖基化，在某些情况下也被羟基化。含有每个可能的脱氧-α-甘露糖对映体的衍生物的合成使我们能够确定天然产物中糖的绝对立体化学，并表明虽然糖基化不会改变抗菌活性，但它确实似乎改善了溶解性。对与其信号肽靶标结合的脂糖肽芳香霉素的晶体结构研究揭示了抑制作用的分子相互作用，以及甘露糖从结合部位进入溶剂，这表明可以在相同的位置进行其他修饰，以进一步增加溶解性，从而减少蛋白质结合，并可能优化支架的药代动力学。
Glycosylation of natural products, including antibiotics, often plays an important role in determining their physical properties and their biological activity, and thus their potential as drug candidates. The arylomycin class of antibiotics inhibits bacterial type I signal peptidase and is comprised of three related series of natural products with a lipopeptide tail attached to a core macrocycle. Previously, we reported the total synthesis of several A series derivatives, which have unmodified core macrocycles, as well as B series derivatives, which have a nitrated macrocycle. We now report the synthesis and biological evaluation of lipoglycopeptide arylomycin variants whose macrocycles are glycosylated with a deoxy-α-mannose substituent, and also in some cases hydroxylated. The synthesis of the derivatives bearing each possible deoxy-α-mannose enantiomer allowed us to assign the absolute stereochemistry of the sugar in the natural product and also to show that while glycosylation does not alter antibacterial activity, it does appear to improve solubility. Crystallographic structural studies of a lipoglycopeptide arylomycin bound to its signal peptidase target reveal the molecular interactions that underlie inhibition and also that the mannose is directed away from the binding site into solvent which suggests that other modifications may be made at the same position to further increase solubility and thus reduce protein binding and possibly optimize the pharmacokinetics of the scaffold.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
--
作者：
Baltz, RH
通讯作者：
Baltz, RH
影响因子：
3.6
作者：
EDGAR, KJ;FALLING, SN
通讯作者：
FALLING, SN
影响因子：
5.1
作者：
Laskaris, Paris;Tolba, Sahar;Wellington, Liz
通讯作者：
Wellington, Liz
DOI：
10.1007/s10295-005-0077-9
发表时间：
2006-07-01
影响因子：
3.4
作者：
Baltz, Richard H.
通讯作者：
Baltz, Richard H.