1398623-71-6Relevant academic research and scientific papers
Glucagon like Peptide 1 Receptor Agonists for Targeted Delivery of Antisense Oligonucleotides to Pancreatic Beta Cell
Knerr, Laurent,Prakash, Thazha P.,Lee, Richard,Drury Iii, William J.,Nikan, Mehran,Fu, Wuxia,Pirie, Elaine,Maria, Leonardo De,Valeur, Eric,Hayen, Ahlke,?lweg?rd-Halvarsson, Maria,Broddefalk, Johan,?mm?l?, Carina,?stergaard, Michael E.,Meuller, Johan,Sundstr?m, Linda,Andersson, Patrik,Janzén, David,Jansson-L?fmark, Rasmus,Seth, Punit P.,Andersson, Shalini
, p. 3416 - 3429 (2021)
The extra hepatic delivery of antisense oligonucleotides (ASOs) remains a challenge and hampers the widespread application of this powerful class of therapeutic agents. In that regard, pancreatic beta cells are a particularly attractive but challenging cell type because of their pivotal role in diabetes and the fact that they are refractory to uptake of unconjugated ASOs. To circumvent this, we have expanded our understanding of the structure activity relationship of ASOs conjugated to Glucagon Like Peptide 1 Receptor (GLP1R) agonist peptide ligands. We demonstrate the key role of the linker chemistry and its optimization to design maleimide based conjugates with improved in vivo efficacy. In addition, truncation studies and scoping of a diverse set of GLP1R agonists proved fruitful to identify additional targeting ligands efficacious in vivo including native hGLP1(7-36)NH2. Variation of the carrier peptide also shed some light on the dramatic impact of subtle sequence differences on the corresponding ASO conjugate performance in vivo, an area which clearly warrant further investigations. We have confirmed the remarkable potential of GLP1R agonist conjugation for the delivery of ASOs to pancreatic beta cell by effectively knocking down islet amyloid polypeptide (IAPP) mRNA, a potential proapoptotic target, in mice.
Syntheses of siderophore-drug conjugates using a convergent thiol-maleimide system
Juarez-Hernandez, Ral E.,Miller, Patricia A.,Miller, Marvin J.
supporting information, p. 799 - 803 (2013/01/15)
Three siderophore-drug conjugates (sideromycins) were synthesized by preparation of a maleimide linked derivative of the siderophore desferrioxamine B and reacting the corresponding Ga3+-complex with freshly prepared thiol-containing antibiotics: loracarbef, ciprofloxacin, and nadifloxacin. The conjugates and their synthetic precursors were tested against a broad panel of bacteria and were found to display Gram-positive selective, growth inhibitory activity (μM), indicating that this approach is suitable for the convergent syntheses and screening of novel sideromycins.
