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Over the past few decades, modified sugars have been incorporated into nucleic acid-based therapeutics to increase their pharmacological potential. Sapala has dedicated significant efforts to developing all possible sugar modifications in nucleic acids, including 2′-O-substituted, 2′-substituted, 3′-O-substituted, 3′-substituted, 4′-substituted, C5′-modification, locked nucleic acids, bicyclo and tricyclo nucleic acids, morpholino nucleic acids, L-nucleosides, 4′-thio nucleosides, acyclic nucleosides, pyranose nucleosides, and threose nucleosides.
Nucleosides containing modified bases, such as purines, pyrimidines, or their analogs, have been widely studied and applied in antiviral and antitumor drugs. In addition, base-modified oligonucleotides and nucleic acids have become popular targets. Sapala has developed synthetic methods for a variety of structurally interesting base-modified nucleosides and nucleotides, including C5-substituted pyrimidines, 7-substituted 7-deaza purines, and C-nucleosides.
The backbone of oligonucleotides refers to the internucleotide linkage. Sapala has experience in synthesizing almost all types of modified monomers for backbone-modified oligonucleotides, including 3′-P-B, 3′-P-S, and diastereopure amidites. Sapala has also demonstrated expertise in synthesizing phosphorothioate (PS) backbones, phosphorodithioate (PdiS) backbones, and P-N backbone-modified oligonucleotides.
Phosphate derivatives of nucleosides, known as nucleotides, include nucleoside monophosphates, nucleoside diphosphates, nucleoside triphosphates, and oligomers of nucleoside monophosphates (oligonucleotides). Sapala has developed robust protocols for synthesizing standard and modified nucleosides in highly pure forms, including Rp- and Sp-isomers of α-Thio NTPs on a gram scale.
The recent FDA approval of mRNA vaccines for COVID-19 highlights the importance of mRNA in therapeutic applications. Sapala has played a significant role in supplying key starting materials such as pseudouridine, N1-methyl pseudouridine, dinucleotide caps (in multi-kilogram quantities), and trinucleotide caps (in gram quantities) with high purity. We continue to develop new dinucleotide and trinucleotide cap analogs.
Oligonucleotides, short DNA or RNA molecules, are chemically synthesized using monomeric building blocks such as protected phosphoramidites of natural or chemically modified nucleosides, succinate-loaded CPG, and PS. Sapala has a fully backward-integrated arrangement for oligo synthesis, including the synthesis of modified nucleosides, phosphoramidites, and in-house production of high-quality reagents. We can synthesize and purify DNA and RNA oligonucleotides with sugar, base, and backbone modifications.
Spacer phosphoramidites are used to position tags or labels at specific lengths from an oligonucleotide, immobilizing them to a solid phase or forming non-nucleoside folds and hairpin loops. Linkers are used to conjugate lipids, peptides, antibodies, and sugars like GalNAc. Sapala has synthesized various types of linkers, including PEG, disulfide, and photocleavable linkers.
Solid-phase chemical synthesis of oligonucleotides using the phosphoramidite approach is a widely used technique. Sapala has expertise in synthesizing universal linkers and nucleoside hemisuccinates and loading them onto CPG and PS. We offer succinate derivatives, including 3′-O-succinate of DNA nucleosides, 2′-substituted RNA nucleosides, and GalNAc succinates.