title: Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential.
abstract: Along with a growing interest in mRNA-based gene therapies, efforts are increasingly focused on reaching the full translational potential of mRNA, as a major obstacle for in vivo applications is sufficient expression of exogenously delivered mRNA. One method to overcome this limitation is chemically modifying the 7-methylguanosine cap at the 5' end of mRNA (m7Gppp-RNA). We report a novel class of cap analogs designed as reagents for mRNA modification. The analogs carry a 1,2-dithiodiphosphate moiety at various positions along a tri- or tetraphosphate bridge, and thus are termed 2S analogs. These 2S analogs have high affinities for translation initiation factor 4E, and some exhibit remarkable resistance against the SpDcp1/2 decapping complex when introduced into RNA. mRNAs capped with 2S analogs combining these two features exhibit high translation efficiency in cultured human immature dendritic cells. These properties demonstrate that 2S analogs are potentially beneficial for mRNA-based therapies such as anti-cancer immunization.
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Zwirki i Wigury 93 Warsaw 02-089, Poland.
authors.forename: Malwina
authors.initials: M
authors.lastname: Strenkowska
authors.affiliation: Centre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Grzela
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Zwirki i Wigury 93 Warsaw 02-089, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Majewski
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Zwirki i Wigury 93 Warsaw 02-089, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Wnek
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Zwirki i Wigury 93 Warsaw 02-089, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kowalska
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Zwirki i Wigury 93 Warsaw 02-089, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Lukaszewicz
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Zwirki i Wigury 93 Warsaw 02-089, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Zuberek
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Zwirki i Wigury 93 Warsaw 02-089, Poland.|Centre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland.
authors.forename: Edward
authors.initials: E
authors.lastname: Darzynkiewicz
authors.affiliation: BioNTech RNA Pharmaceuticals GmbH, An der Goldgrube 12, 55131 Mainz, Germany.|Translational Oncology (TRON), Freiligrathstraße 12, 55131 Mainz, Germany.
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Kuhn
authors.affiliation: BioNTech RNA Pharmaceuticals GmbH, An der Goldgrube 12, 55131 Mainz, Germany.|Translational Oncology (TRON), Freiligrathstraße 12, 55131 Mainz, Germany.
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
authors.affiliation: Centre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland jacekj@biogeo.uw.edu.pl.
authors.forename: Jacek
authors.initials: J
authors.lastname: Jemielity
mesh_terms: D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells; D011756:Diphosphates / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D014176:Protein Biosynthesis; D012314:RNA Cap Analogs / Q000138:chemical synthesis; D012315:RNA Caps; D012333:RNA, Messenger / Q000737:chemistry* / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D011756:Diphosphates; C111931:ELF4 protein, human; D012314:RNA Cap Analogs; D012315:RNA Caps; D012333:RNA, Messenger; D014157:Transcription Factors