肽缀合蝶呤作为蓖麻毒素 A 的抑制剂。
Peptide-conjugated pterins as inhibitors of ricin toxin A.
机构信息
Department of Chemistry, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Japan.
出版信息
J Med Chem. 2013 Jan 10;56(1):320-9. doi: 10.1021/jm3016393. Epub 2012 Dec 19.
Abstract
Several 7-peptide-substituted pterins were synthesized and tested as competitive active-site inhibitors of ricin toxin A (RTA). Focus began on dipeptide conjugates, and these results further guided the construction of several tripeptide conjugates. The binding of these compounds to RTA was studied via a luminescence-based kinetic assay, as well as through X-ray crystallography. Despite the relatively polar, solvent exposed active site, several hydrophobic interactions, most commonly π-interactions not predicted by modeling programs, were identified in all of the best-performing inhibitors. Nearly all of these compounds provide IC₅₀ values in the low micromolar range.
摘要
几种七肽取代蝶呤被合成并作为蓖麻毒素 A（RTA）的竞争性活性部位抑制剂进行了测试。研究重点放在二肽缀合物上，这些结果进一步指导了几种三肽缀合物的构建。通过基于发光的动力学测定以及 X 射线晶体学研究了这些化合物与 RTA 的结合。尽管活性部位相对极性，溶剂暴露，但在所有表现最佳的抑制剂中均鉴定出几种疏水性相互作用，最常见的是建模程序未预测到的π-相互作用。几乎所有这些化合物的 IC₅₀ 值都在低微摩尔范围内。
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1
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2
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3
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Toxins (Basel). 2012 Jan;4(1):15-27. doi: 10.3390/toxins4010015. Epub 2012 Jan 6.
4
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Toxins (Basel). 2011 Sep;3(9):1163-84. doi: 10.3390/toxins3091163. Epub 2011 Sep 15.
5
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7
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