Modified nucleosides, nucleotides, and nucleic acids, and uses thereof

A method of synthesizing a messenger ribonucleic acid (mRNA), comprising the steps of:

• a) providing a complementary deoxyribonucleic acid (cDNA) that encodes a pharmaceutical protein of interest;
• b) selecting a nucleotide that disrupts a binding of a major groove binding partner with the RNA, wherein the nucleotide has decreased binding affinity to the major groove binding partner selected from the group consisting of toll-like receptor (TLR) 3, TLR7, TLR8, retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), and wherein the nucleotide comprises a modification on the major groove face of the nucleobase where an atom of the major groove face of the nucleobase is replaced or substituted with an alkyl group;
• c) contacting the provided cDNA and the selected nucleotide with an RNA polymerase under conditions such that an RNA transcript is synthesized, and
• d) 5′-capping the RNA transcript concomitantly or post-transcriptionally such that the mRNA is synthesized.