Trinucleotide Cap Analogue Bearing a Locked Nucleic Acid Moiety: Synthesis, mRNA Modification, and Translation for Therapeutic Applications

Senthilvelan, Annamalai; Vonderfecht, Tyson; Shanmugasundaram, Muthian; Pal, Indra; Potter, Jason; Kore, Anilkumar R.

doi:10.1021/acs.orglett.1c01037

Cited by 20 publications

(30 citation statements)

References 26 publications

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“…In this context, we have reported a synthesis of novel trinucleotide cap analog bearing an LNA moiety and studied its capping efficiency and translational efficiency. [50] The required intermediate, m 7(LNA) ImGDP 138 for the synthesis of LNA tricap, m 7(LNA) G(5′)ppp(5′)( 2′‐OMe A)pG 143 was obtained in seven steps, starting from 5′‐DMT‐ N ‐DMF LNA guanosine 131 as depicted in Scheme 21 . The detritylation of 131 using 3 % trichloroacetic acid in dichloromethane, followed by the deprotection of DMF group using 1 : 1 mixture of aqueous 40 % methylamine and 28 % ammonium hydroxide afforded LNA guanosine 133 .…”

Section: Chemical Synthesis Of Cap Analogsmentioning

confidence: 99%

“…We envisaged that the design of a new trinucleotide cap analog bearing an LNA moiety could act as a potential molecular biology tool in the area of mRNA transfection applications such as anticancer immunization, protein production, and gene therapy and mRNA‐based vaccines. In this context, we have reported a synthesis of novel trinucleotide cap analog bearing an LNA moiety and studied its capping efficiency and translational efficiency [50] . The required intermediate, m 7(LNA) ImGDP 138 for the synthesis of LNA tricap, m 7(LNA) G(5′)ppp(5′)( 2′‐OMe A)pG 143 was obtained in seven steps, starting from 5′‐DMT‐ N ‐DMF LNA guanosine 131 as depicted in Scheme 21.…”

Section: Chemical Synthesis Of Cap Analogsmentioning

confidence: 99%

“…The capping efficiency of new LNA tricap 143 was performed in an in vitro transcription system by using an IVT template encoding GFP to produce transcripts of ∼1000 nucleotides in length with a synthetic 5′‐UTR, a mouse alpha globin 3′‐UTR, and a 120 nucleotide poly(A) tail [50] . The outcome of the assay reveals that LNA cap 143 has a capping efficiency of 53 %, indicating this LNA tricap is a good substrate for T7 RNA polymerase.…”

Section: Biological Applications Of Cap Analogsmentioning

confidence: 99%

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Recent Advances in Modified Cap Analogs: Synthesis, Biochemical Properties, and mRNA Based Vaccines

Shanmugasundaram

Senthilvelan

Kore

2022

The Chemical Record

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The recent FDA approval of the mRNA vaccine for severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) emphasizes the importance of mRNA as a powerful tool for therapeutic applications. The chemically modified mRNA cap analogs contain a unique cap structure, m 7 G[5′]ppp[5′]N (where N=G, A, C or U), present at the 5′‐end of many eukaryotic cellular and viral RNAs and several non‐coding RNAs. The chemical modifications on cap analog influence orientation's nature, translational efficiency, nuclear stability, and binding affinity. The recent invention of a trinucleotide cap analog provides groundbreaking research in the area of mRNA analogs. Notably, trinucleotide cap analogs outweigh dinucleotide cap analogs in terms of capping efficiency and translational properties. This review focuses on the recent development in the synthesis of various dinucleotide cap analogs such as dinucleotide containing a triazole moiety, phosphorothiolate cap, biotinylated cap, cap analog containing N1 modification, cap analog containing N2 modification, dinucleotide containing fluorescence probe and TAT, bacterial caps, and trinucleotide cap analogs. In addition, the biological applications of these novel cap analogs are delineated.

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Section: Chemical Synthesis Of Cap Analogsmentioning

confidence: 99%

Section: Chemical Synthesis Of Cap Analogsmentioning

confidence: 99%

Section: Biological Applications Of Cap Analogsmentioning

confidence: 99%

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Recent Advances in Modified Cap Analogs: Synthesis, Biochemical Properties, and mRNA Based Vaccines

Shanmugasundaram

Senthilvelan

Kore

2022

The Chemical Record

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“…( Warminski et al, 2013 ; Shanmugasundaram et al, 2016 ; Dülmen et al, 2021 ; Wojcik et al, 2021 ) Locked nucleic acid (LNA) caps have also been investigated, in which the ribose is locked in an C3′-endo conformation by a bridging methylene group between the 2′ oxygen and 4′ carbon ( Kore et al, 2009 ). Although LNAs have primarily been used in oligonucleotides, mRNAs capped by an LNA analog have recently been demonstrated to have increased translational efficiency and stability ( Senthilvelan et al, 2021 ). Given the promise many of these modifications have demonstrated in in vitro experiments, the optimization of capped mRNAs using these analogs in vivo and in clinical applications holds promise for even more effective future drugs.…”

Section: Stability and Translational Efficiency Of Mrnamentioning

confidence: 99%

The Pivotal Role of Chemical Modifications in mRNA Therapeutics

Liu

Wang

2022

Front. Cell Dev. Biol.

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After over a decade of development, mRNA has recently matured into a potent modality for therapeutics. The advantages of mRNA therapeutics, including their rapid development and scalability, have been highlighted due to the SARS-CoV-2 pandemic, in which the first two clinically approved mRNA vaccines have been spotlighted. These vaccines, as well as multiple other mRNA therapeutic candidates, are modified to modulate their immunogenicity, stability, and translational efficiency. Despite the importance of mRNA modifications for harnessing the full efficacy of mRNA drugs, the full breadth of potential modifications has yet to be explored clinically. In this review, we survey the field of mRNA modifications, highlighting their ability to tune the properties of mRNAs. These include cap and tail modifications, nucleoside substitutions, and chimeric mRNAs, each of which represents a component of mRNA that can be exploited for modification. Additionally, we cover clinical and preclinical trials of the modified mRNA platform not only to illustrate the promise of modified mRNAs but also to call attention to the room for diversifying future therapeutics.

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“…Lately, advancements in capping technology have yielded candidates that can outperform ARCAs. Such an example is the development of trinucleotide caps containing locked nucleic acid analogues which can increase translational efficiency of modified mRNAs by a factor of 5 compared to ARCAs as well as GAG cap in the mouse dendritic JAWSII cell line [ 201 ].…”

Section: Mrna Stability and Modificationsmentioning

confidence: 99%

mRNA Therapeutic Modalities Design, Formulation and Manufacturing under Pharma 4.0 Principles

et al. 2021

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In the quest for a formidable weapon against the SARS-CoV-2 pandemic, mRNA therapeutics have stolen the spotlight. mRNA vaccines are a prime example of the benefits of mRNA approaches towards a broad array of clinical entities and druggable targets. Amongst these benefits is the rapid cycle “from design to production” of an mRNA product compared to their peptide counterparts, the mutability of the production line should another target be chosen, the side-stepping of safety issues posed by DNA therapeutics being permanently integrated into the transfected cell’s genome and the controlled precision over the translated peptides. Furthermore, mRNA applications are versatile: apart from vaccines it can be used as a replacement therapy, even to create chimeric antigen receptor T-cells or reprogram somatic cells. Still, the sudden global demand for mRNA has highlighted the shortcomings in its industrial production as well as its formulation, efficacy and applicability. Continuous, smart mRNA manufacturing 4.0 technologies have been recently proposed to address such challenges. In this work, we examine the lab and upscaled production of mRNA therapeutics, the mRNA modifications proposed that increase its efficacy and lower its immunogenicity, the vectors available for delivery and the stability considerations concerning long-term storage.

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Trinucleotide Cap Analogue Bearing a Locked Nucleic Acid Moiety: Synthesis, mRNA Modification, and Translation for Therapeutic Applications

Cited by 20 publications

References 26 publications

Recent Advances in Modified Cap Analogs: Synthesis, Biochemical Properties, and mRNA Based Vaccines

Recent Advances in Modified Cap Analogs: Synthesis, Biochemical Properties, and mRNA Based Vaccines

The Pivotal Role of Chemical Modifications in mRNA Therapeutics

mRNA Therapeutic Modalities Design, Formulation and Manufacturing under Pharma 4.0 Principles

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