Organic Synthesis and Improved Biological Properties of Modified mRNA Cap Analogs

The aim of this review is to emphasize the importance of modified dinucleotide cap analogs and their useful biological and therapeutic applications. Dinucleoside 5'-5'-triphosphates fulfill numerous regulatory, signaling, or energetic functions (mRNA metabolism- synthesis, nucleo-cytoplasmic transport, translation, silencing, and turnover) in biological systems. In this context, we highlight the recent studies on the improvement in the design, synthesis and biological application of chemically synthesized cap analogs. The 5'- terminus of eukaryotic messenger RNA (mRNA) molecules contain a unique 'cap' structure: 7-methylguanosine (m7G) linked by a 5'-5'- triphosphate bridge to the first nucleoside in the standard polymer chain. This 5'-cap is recognized by numerous enzymes involved in the transport and translation of mRNA, as well as its processing, both in terms of generating mature mRNA from the initial transcript and its mRNA turnover. These chemically modified cap analogs are mostly anti-reverse cap analogs (ARCA) variants that result in a forward oriented cap structure after their incorporation into mRNA. The recent chemical modifications on 7-methylguanosine (m7G) either at 2' or 3' hydroxyl group with -OCH3, -fluoro, -2' or 3' deoxy G, conformationaly constrained cap modifications such as -2', 3' isopropyledene or LNA substitutions, and triphosphate bridge modifications are discussed along with their biological significance. Due to their relevance in biological processes, the 5'-capped mRNA poly(A) with modified dinucleotide analogs have attracted considerable interest in biotechnology. This review focuses on the recent development of synthetic dinucleotide cap analogs, which are widely employed as tools for studying physiological processes as well as ARCA capped mRNA's potential use in clinical applications are discussed.