Uniwersytet Warszawski

Louisiana State University and Agricultural & Mechanical College

Biontech Ag

Tron—translationale Onkologie An Der Universitátsmedizin Der Johannes Gutenberg—universitÄt Mainz Gemeinnützige Gmbh

University of Warsaw

Jacek Jemielity

Joanna Kowalska

Edward Darzynkiewicz

Robert E Rhoads

Ugur Sahin

Andreas Kuhn

Kaja Fac-Da̧browska

Ewa M Grudzien-Nogalska

Joanna Zuberek

Maciej Lukaszewicz

Sylwia Walczak

Marcin Warmiński

Paweł Sikorski

Anna Nowicka

Marek Baranowski

Blażej Wojtczak

Marcin Warminski

Pawel Sikorski

Kaja Fac-Dabrowska

Blazej Wojtczak

The present invention relates to nucleotides, analogs of mRNA 5'-end (cap) containing sulfur atom at the position 5&#x2032; of 7-methylguanosine nucleoside. The disclosed compounds are recognized (bound and non-hydrolyzed) by DcpS enzyme (Decapping Scavenger), and thus may find therapeutic use as inhibitors thereof. DcpS is cap-specific enzyme with pyrophosphatase activity, which was identified as a therapeutic target in the treatment of spinal muscular atrophy (SMA). Some of the compounds disclosed have additional modifications in the phosphate chain, which modulate their affinity for DcpS enzyme. The present invention also relates to mRNAs modified at the 5&#x2032; end with mRNA 5&#x2032;-end (cap) analogs containing 5&#x2032;-phosphorothiolate moiety, which mRNAs have an increased stability and translational activity in cellular conditions, to a method of their preparation, their uses, and to a pharmaceutical formulation containing them, wherein Land Lare independently selected from the group comprising O and S, wherein at least one of Land Lis not O. 

5'-phosphorothiolate mRNA 5&#x2032;-end (cap) analogs, mRNA comprising the same, method of obtaining and uses thereof

The object of the invention is a compound of formula (I), or a stereoisomer or salt thereof, wherein Rand Rare selected from the group consisting of N, N+&#x2014;CH, N&#x2014;CH, N&#x2014;CH, N&#x2014;CH, N&#x2014;CHCHwherein at least one of R, Ris not N. n and m are independently chosen from the group consisting of 0, 1 and 2; X is selected from the group consisting of O, NH, S, CHk is 1 or 2 Y is either void or selected from the group of &#x2014;CH&#x2014;, &#x2014;CHCH&#x2014;, &#x2014;CHO&#x2014;, &#x2014;CHS&#x2014;, &#x2014;CHNH&#x2014;, &#x2014;CHCHO&#x2014;, &#x2014;CHCHNH&#x2014;, &#x2014;CHCHS&#x2014; R, R, R, Rare selected from the group consisting of H, OH, OCH, or OCHCH; wherein Rand Rmay be the same or different; Rand Rmay be the same or different; if either of R, Ris different than OH than Rand Rare both OH; if either of R, Ris different than OH than Rand Rare both OH. The object of the invention is also a composition comprising the compound of the invention, an RNA molecule incorporating the same, uses thereof and a method of synthesizing, in vitro or in vivo, the RNA molecule, as well as a method of synthesizing a protein or peptide in vitro, or in vivo or in cultured cells, said method comprising translating the RNA molecule. 

Phosphotriazole MRNA 5'-end cap analogs, composition comprising the same, RNA molecule incorporating the same, uses thereof and method of synthesizing RNA molecule, protein or peptide

The present invention relates to modification of RNA with 5'-cap analogs of Formula (1): wherein R-Rand n are as described herein, in order to improve the stability and increase the expression of said RNA, in particular in immature antigen presenting cells. The present invention provides a vaccine composition comprising said stabilized RNA, immature antigen presenting cells comprising said stabilized RNA, and methods for stimulating and/or activating immune effector cells and for inducing an immune response in an individual using said stabilized RNA.

Vaccine composition comprising 5'-cap modified RNA

Dinucleotide cap analogs are disclosed, modified at different phosphate positions with a boranophosphate group or a phosphoroselenoate group. The analogs are useful as reagents in the preparation of capped mRNAs and have increased stability both in vitro and in vivo. They may be used as inhibitors of cap-dependent translation. Optionally, the boranophosphate or phosphoroselenoate group has a 2'-O or 3&#x2032;-O-alkyl group, preferably a methyl group, producing analogs called BH-ARCAs or Se-ARCAs. ARCAs may be modified with &#x3b1;-, &#x3b2;-, or &#x3b3;-boranophosphate or phosphoroselenoate groups.

mRNA cap analogs

New RNA cap analogs are disclosed containing one or more phosphorothioates groups. The analogs also contain modifications at the 2'-O position of 7-methylguanosine that prevent them from being incorporated in the reverse orientation during in vitro synthesis of mRNA and that hence are 'anti-reverse cap analogs' (ARCAs). The ARCA modification ensures that the S atom is precisely positioned within the active sites of cap-binding proteins in both the translational and decapping machinery. The new S-ARCA analogs are resistant to in vivo decapping enzymes. Some S-ARCAs have a higher affinity for eIF4E than the corresponding analogs not containing a phosphorothioate group. When mRNAs containing the various S-ARCAs are introduced into cultured cells, some are translated as much as five-fold more efficiently than mRNAs synthesized with the conventional analog mGpppG.

Synthesis and use of anti-reverse phosphorothioate analogs of the messenger RNA cap

Growing community of inventors

Warsaw, Poland

Jacek Jemielity