Targeted tissue delivery of RNA therapeutics using antibody-oligonucleotide conjugates (AOCs).

Although targeting TfR1 to deliver oligonucleotides to skeletal muscle has been demonstrated in rodents, effectiveness and pharmacokinetic/pharmacodynamic (PKPD) properties remained unknown in higher species. We developed antibody-oligonucleotide conjugates (AOCs) towards mice or monkeys utilizing anti-TfR1 monoclonal antibodies (αTfR1) conjugated to various classes of oligonucleotides (siRNA, ASOs and PMOs). αTfR1 AOCs delivered oligonucleotides to muscle tissue in both species. In mice, αTfR1 AOCs achieved a > 15-fold higher concentration to muscle tissue than unconjugated siRNA. A single dose of an αTfR1 conjugated to an siRNA against Ssb mRNA produced > 75% Ssb mRNA reduction in mice and monkeys, and mRNA silencing was greatest in skeletal and cardiac (striated) muscle with minimal to no activity in other major organs. In mice the EC50 for Ssb mRNA reduction in skeletal muscle was >75-fold less than in systemic tissues. Oligonucleotides conjugated to control antibodies or cholesterol produced no mRNA reduction or were 10-fold less potent, respectively. Tissue PKPD of AOCs demonstrated mRNA silencing activity primarily driven by receptor-mediated delivery in striated muscle for siRNA oligonucleotides. In mice, we show that AOC-mediated delivery is operable across various oligonucleotide modalities. AOC PKPD properties translated to higher species, providing promise for a new class of oligonucleotide therapeutics.

Supported imidazolylphosphine catalysts for highly (E)-selective alkene isomerization.

For fine chemical synthesis, immobilized catalysts offer little advantage if they produce a product mixture that must be separated. Selective isomerization of terminal olefins is achieved by heterogenized bifunctional catalysts. Outstanding and consistent (E)-selectivity (>99%) even in cases where (E) and (Z) isomers are of comparable stability, combined with modest catalyst loadings (1 to 2 mol %), set these catalysts apart from previously reported systems. Ease of catalyst removal and high geometric selectivity avoid tedious purifications.

General catalyst control of the monoisomerization of 1-alkenes to trans-2-alkenes.

After searching for the proper catalyst, the dual challenges of controlling the position of the double bond, and cis/trans-selectivity in isomerization of terminal alkenes to their 2-isomers are finally met in a general sense by mixtures of (C5Me5)Ru complexes 1 and 3 featuring a bifunctional phosphine. Typically, catalyst loadings of 1 mol % of 1 and 3 can be employed for the production of (E)-2-alkenes at 40-70 °C. Catalyst comprising 1 and 3 avoids more than any other known example the thermodynamic equilibration of alkene isomers, as the trans-2-alkenes of both nonfunctionalized and functionalized alkenes are generated.

Mild and selective deuteration and isomerization of alkenes by a bifunctional catalyst and deuterium oxide.

H/D exchange is achieved at allylic positions of alkenes using D(2)O in acetone and alkene isomerization catalyst 1, which features a bifunctional imidazolylphosphine. The basic nitrogen of the latter is thought to deprotonate an alkene substrate coordinated to the CpRu center; at this stage the protonated nitrogen could undergo H/D exchange with deuterium oxide. An exceptional degree of deuteration is achieved at positions accessible to isomerization, with a high degree of control. Using biphasic settings one can literally wash out reactive protons on the substrate without using organic solvents.

Hydrogen-bond acceptance of bifunctional ligands in an alkyne-metal pi complex.

Experiment and theory have been used to study reactive alkyne pi complexes, intermediates in anti-Markovnikov alkyne hydration by CpRu bis(phosphine) catalysts with heterocyclic substituents. Each heterocycle accepts a hydrogen bond from an acetylene C-H, as revealed by NMR coupling constants between alkyne 13C and 1H nuclei as well as between alkyne 13C and pyridine 15N (2hJCN). Moreover, further alkyne transformations occur at temperatures from 50 to 90 degrees C below what is needed to convert a control compound without the heterocycles.