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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; Ölwegård-Halvarsson, Maria; Broddefalk, Johan; Ämmälä, Carina; Østergaard, Michael E; Meuller, Johan; Sundström, Linda; Andersson, Patrik; Janzén, David; Jansson-Löfmark, Rasmus; Seth, Punit P; Andersson, Shalini.
Afiliación
  • Knerr L; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Prakash TP; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, California 92010, United States.
  • Lee R; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, California 92010, United States.
  • Drury Iii WJ; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Nikan M; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, California 92010, United States.
  • Fu W; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, California 92010, United States.
  • Pirie E; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, California 92010, United States.
  • Maria L; Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Valeur E; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Hayen A; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Ölwegård-Halvarsson M; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Broddefalk J; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Ämmälä C; Bioscience, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Østergaard ME; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, California 92010, United States.
  • Meuller J; Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • Sundström L; Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • Andersson P; Respiratory and Immunology Safety, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • Janzén D; DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Jansson-Löfmark R; DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Seth PP; Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, California 92010, United States.
  • Andersson S; Research and early Development, Discovery Sciences,, AstraZeneca, Gothenburg, Sweden.
J Am Chem Soc ; 143(9): 3416-3429, 2021 03 10.
Article en En | MEDLINE | ID: mdl-33626278
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Portadores de Fármacos / Oligonucleótidos Antisentido / Células Secretoras de Insulina / Receptor del Péptido 1 Similar al Glucagón Límite: Animals / Humans Idioma: En Revista: J Am Chem Soc Año: 2021 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Portadores de Fármacos / Oligonucleótidos Antisentido / Células Secretoras de Insulina / Receptor del Péptido 1 Similar al Glucagón Límite: Animals / Humans Idioma: En Revista: J Am Chem Soc Año: 2021 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Estados Unidos