Apr 29, 2019 · Here, we report that toxic gapmer PS-ASOs containing modifications such as constrained ethyl (cEt), locked nucleic acid (LNA) and 2′- O -methoxyethyl (2′-MOE) bind many cellular proteins with...

Combining the structural elements of the second generation 2′- O -methoxyethyl (MOE) and locked nucleic acid (LNA) antisense oligonucleotide (AON) modifications yielded the highly nuclease resistant 2′,4′-constrained MOE and ethyl bicyclic nucleic acids …

Feb 8, 2010 · We have recently shown that combining the structural elements of 2′O-methoxyethyl (MOE) and locked nucleic acid (LNA) nucleosides yielded a series of nucleoside modifications (cMOE, 2′,4′-constrained MOE; cEt, 2′,4′-constrained ethyl) that display improved potency over MOE and an improved therapeutic index relative to that of LNA ...

在之前讲Inotersen的文章中，我们提到Ionis的第二代MOE gapmer反义寡核苷酸 (ASO)药物，其中MOE和gapmer修饰分别是为了提高寡核苷酸药物的药代动力学和效能。 cEt ( (S)-constrained ethyl)包含另一种糖基取代，形成双环核苷结构， 这种取代相比于MOE gapmer ASO的效能提高了约10倍。 cEt技术是Ionis目前最先进的反义技术之一，用于生产下一代ASO分子，称之为Generation 2.5。 得益于cEt更高的效力， 使用cEt技术开发的药物能够作用于更广泛的组织靶标。

The higher stabilization of RNA can be attributed to the preorganization of LNA nucleosides towards formation of A-form duplexes , whereas in DNA duplexes LNA residues steer the conformation of the neighboring DNA monomers into the C3'-endo conformation [135–136].

PS linkages stabilize ASOs against nuclease activity, increasing their plasma half-life to up to 1 h. Chemical modification of the 2′ position with MOE, cEt, or LNA eliminates exonuclease activity, extending tissue elimination half-life to four weeks.

Apr 1, 2019 · cET = contrained ethyl; MOE = 2′ O -methoxyethyl; LNA = locked nucleic acid. Please see the text for descriptions of the structures. Modifications to the oligonucleotide phosphate linkages predominantly assist in nuclease avoidance.

Mar 2, 2018 · Some 2′-sugar modifications, including locked nucleic acid (LNA) and constrained ethyl (cEt) substitutions, significantly increase the binding affinity of RNase H1-activating gapmer ASOs, i.e., ASOs containing a central deoxynucleotide region flanked on both ends by several modified ribonucleotides.

Oct 10, 2017 · Each MOE or OMe modification increases the melting temperature of an ASO–RNA duplex by 0.5–1°C, whereas F and 2′4’-bridged nucleic acids such as LNA and cEt stabilize duplex interactions to a greater extent (1–2.5°C per modification for F and 3–5°C per modification for LNA and cEt) ( 14, 19 – 21 ).

Biophysical evaluation revealed that the cMOE and cEt modifications hybridize complementary nucleic acids with the same affinity as LNA while greatly increasing nuclease stability.