Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides.
Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides.
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DOI：
10.1093/nar/gkab718
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发表时间：
2021-09-20
影响因子：
14.9
通讯作者：
Seth PP
中科院分区：
文献类型：
--
作者：
Anderson BA;Freestone GC;Low A;De-Hoyos CL;Iii WJD;Østergaard ME;Migawa MT;Fazio M;Wan WB;Berdeja A;Scandalis E;Burel SA;Vickers TA;Crooke ST;Swayze EE;Liang X;Seth PP
PS修饰增强了gapmer反义寡核苷酸（ASO）的核酸酶稳定性和蛋白质结合特性，并且是支持RNaseH 1活性的极少数修饰之一。我们评估了在缺口聚体PS ASO的DNA缺口和侧翼中引入立构无规和手性甲磺酰基-氨基磷酸酯（MsPA）键的作用，并表征了这些键对细胞和小鼠中的RNA结合、核酸酶稳定性、蛋白结合、促炎性特征、反义活性和毒性的作用。我们表明，所有的PS连接在一个缺口体阿索可以取代MsPA，而不损害化学稳定性和RNA结合亲和力，但这些设计降低了活性。然而，用MsPA替换差距中的多达5个PS是良好耐受的，并且在适当位置替换特异性PS连接能够大大降低免疫刺激和细胞毒性。MsPA相对于PS的改善的核酸酶稳定性转化为小鼠中阿索作用的持续时间的显著改善，这与增强的稳定化siRNA设计的持续时间相当。我们的工作突出了PS和MsPA连接的组合作为下一代化学平台，用于鉴定具有改善的效力和治疗指数、降低的促炎作用和延长的作用持续时间的阿索药物。下一代反义寡核苷酸：甲磺酰氨基磷酸酯修饰改善gapmer反义寡核苷酸的治疗指数和作用持续时间。
The PS modification enhances the nuclease stability and protein binding properties of gapmer antisense oligonucleotides (ASOs) and is one of very few modifications that support RNaseH1 activity. We evaluated the effect of introducing stereorandom and chiral mesyl-phosphoramidate (MsPA) linkages in the DNA gap and flanks of gapmer PS ASOs and characterized the effect of these linkages on RNA-binding, nuclease stability, protein binding, pro-inflammatory profile, antisense activity and toxicity in cells and in mice. We show that all PS linkages in a gapmer ASO can be replaced with MsPA without compromising chemical stability and RNA binding affinity but these designs reduced activity. However, replacing up to 5 PS in the gap with MsPA was well tolerated and replacing specific PS linkages at appropriate locations was able to greatly reduce both immune stimulation and cytotoxicity. The improved nuclease stability of MsPA over PS translated to significant improvement in the duration of ASO action in mice which was comparable to that of enhanced stabilized siRNA designs. Our work highlights the combination of PS and MsPA linkages as a next generation chemical platform for identifying ASO drugs with improved potency and therapeutic index, reduced pro-inflammatory effects and extended duration of effect. Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides.
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影响因子：
5.8
作者：
Crooke, Stanley T.;Liang, Xue-hai;Geary, Richard S.
通讯作者：
Geary, Richard S.
影响因子：
14.9
作者：
Liang, Xue-hai;Sun, Hong;Crooke, Stanley T.
通讯作者：
Crooke, Stanley T.
DOI：
10.1073/pnas.1813376116
发表时间：
2019-01-22
影响因子：
11.1
作者：
Miroshnichenko, S. K.;Patutina, O. A.;Stetsenko, D. A.
通讯作者：
Stetsenko, D. A.
影响因子：
4.2
作者：
Prakash, Thazha P.;Yu, Jinghua;Seth, Punit P.
通讯作者：
Seth, Punit P.
DOI：
10.1124/jpet.105.084004
发表时间：
2005-09-01
影响因子：
3.5
作者：
Senn, JJ;Burel, S;Henry, SP
通讯作者：
Henry, SP