Special (lipid) delivery: The role of the ionizable lipid pKa in the in vivo delivery of siRNA by lipid nanoparticles has been studied with a large number of head group modifications to the lipids. A tight correlation between the lipid pKa value and silencing of the mouse FVII gene (FVII ED50) was found, with an optimal pKa range of 6.2–6.5 (see graph). The most potent cationic lipid from this study has ED50 levels around 0.005 mg kg−1 in mice and less than 0.03 mg kg−1 in non‐human primates.

Der Einfluss des pKS‐Werts von ionisierbaren Lipiden auf den siRNA‐Transport durch Lipidnanopartikel in vivo wurde anhand zahlreicher Modifikationen der Lipid‐Kopfgruppen studiert. Dabei wurde ein Zusammenhang zwischen pKS‐Wert und Stummschaltung des Maus‐FVII‐Gens (FVII ED50) gefunden: pKS‐Werte von 6.2–6.5 erwiesen sich als optimal (siehe Diagramm). Für das wirksamste kationische Lipid betrug ED50 etwa 0.005 mg kg−1 in Mäusen und <0.03 mg kg−1 in Primaten (außer Menschen).

Quantifiable amounts of HOOOH can be detected by 1H NMR spectroscopic analysis of the thermal reaction of O3 and HOOH (see scheme). This first experimental report of a link between these three oxidants suggests that HOOOH may be involved in oxidation reactions that span biological, atmospheric, and environmental systems.

To mL eedom, Mark Foster,a nd Curt W. Bradshaw [a] Oligonucleotides are important therapeutic approaches, as evidenced by recent clinicals uccesses with antisense oligonucleotides (ASOs)a nd double-stranded short interfering RNAs (siRNAs). Phosphorothioate (PS) modifications are as tandard feature in the current generation of oligonucleotide therapeutics, but generatei someric mixtures, leadingt o2 n isomers. All currently marketed therapeutic oligonucleotides (ASOs and siRNAs)a re complex isomeric mixtures. Recent chemical methodologiesf or stereopure PS insertions have resulted in preliminary rules for ASOs, with multiple stereopure ASOs moving into clinicald evelopment. Although siRNAs have comparatively fewer PSs, the field has yet to embrace the idea of stereopure siRNAs.H erein, it has been investigated whether the individual isomersc ontributee qually to the in vivo activity of ar epresentative siRNA. The results of as ystematic evaluation of stereopure PS incorporation into antithrombin-3 (AT3) siRNA are reported and demonstrate that individualP Sisomersd ramatically affect in vivo activity.Astandard siRNA design with six PS insertions was investigated and it was found that only about 10 %o ft he 64 possible isomersw ere as efficacious as the stereorandomc ontrol.B ased on this data, it can be concluded that G1R stereochemistry is critical, G2R is important,G 21S is preferable, and G22 and P1/P2 tolerate both isomers. Surprisingly,t he disproportionate loss of efficacy for most isomers does not translate into significant gain for the productive isomers, and thus, warrants further mechanistic studies.Since the discovery by Fire and Mello in 1998 that doublestranded short interfering RNA (siRNA) can cleave mRNA and inhibit protein translation, [1] this new class of therapeutics has moved towards clinical utility.T he advent of double-stranded siRNAs as am odality to harnessanatural catalytic pathway, called RNA interference (RNAi), excited scientific and business communities alike because of its implications in therapeutics, particularly for targets difficult to drug with small-molecules and proteins. [2] Interesti ns iRNAs has had periodic boom and bust cycles following the recognition of and solutions for technical challenges. One of the significant challenges is delivery of these large, charged siRNA molecules across the cell membrane.B oth lipid nanoparticle and ligand-based approaches are clinically validated, with ar ecent approvalo ft he first RNAi therapeutic, Patisiran, al ipid complex from Alnylam, and nu-merousG alNAc-targeteds iRNAs in clinical trials. [3] Naturally occurring siRNA molecules have two complementary strands (19b ase pairs), with an additional two unpaired bases at the 3'-ends, so-called 21/21. Aw ide variety of variations weree xploredi ne arly optimization, includings ignificant modifications in size (19-to 27-mers) and shape (Dicer-substrate siRNA, asymmetric and blunt-ended designs). [4] In addition, siRNA components, such as sugars,n ucleobases, and the phosphate backbon...

Chelation of Cu(I) ions to an immobilized hydrophilic tris(triazolylmethyl)amine chelator on a solid support allowed synthesis of RNA oligonucleotide conjugates from completely deprotected alkyne-oligonucleotides. No oligonucleotide strand degradation or metal ion contamination was observed. Furthermore, use of the immobilized copper(I) ion overcame regioselectivity issues associated with strain-promoted copper-free azide-alkyne cycloaddition.