1 SomaLogic, Inc. , Boulder, Colorado.
2 Otsuka Pharmaceutical Co., Ltd. , Tokushima, Japan .
Nucleic Acid Ther. 2017 Dec;27(6):345-353. doi: 10.1089/nat.2017.0683. Epub 2017 Sep 29.
The addition of novel side chains at the 5-position of uracil is an effective means to increase chemical diversity of aptamers and hence the success rate for discovery of high-affinity ligands to protein targets. Such modifications also increase nuclease resistance, which is useful in a range of applications, especially for therapeutics. In this study, we assess the impact of these side chains on plasma pharmacokinetics of modified aptamers conjugated to a 40 kDa polyethylene glycol. We show that clearance from plasma depends on relative hydrophobicity: side chains with a negative cLogP (more hydrophilic) result in slower plasma clearance compared with side chains with a positive cLogP (more hydrophobic). We show that clearance increases with the number of side chains in sequences of ≥28 synthons, but this effect is dramatically diminished in shorter sequences. These results serve as a guide for the design of new therapeutic aptamers with diversity-enhancing side chains.
在尿嘧啶的 5 位添加新的侧链是增加适体化学多样性的有效手段，从而提高与蛋白质靶标高亲和力配体的发现成功率。这种修饰还增加了核酸酶抗性，这在一系列应用中非常有用，特别是在治疗学中。在这项研究中，我们评估了这些侧链对与 40 kDa 聚乙二醇缀合的修饰适体的血浆药代动力学的影响。我们表明，从血浆中的清除率取决于相对疏水性：具有负 cLogP（更亲水）的侧链与具有正 cLogP（更疏水）的侧链相比，导致更慢的血浆清除率。我们表明，清除率随序列中≥28 个同义子的侧链数量增加而增加，但在较短的序列中，这种效应显著降低。这些结果为设计具有多样性增强侧链的新型治疗适体提供了指导。
