Skip to main content

Modified Nucleosides as RNA Components. Structure, Biological Role and Drug Design

  • Chapter
  • First Online:
RNA Structure and Function

Part of the book series: RNA Technologies ((RNATECHN,volume 14))

  • 669 Accesses

Abstract

More than 100 modified nucleosides with different structures and functions are known as components of nucleic acids. Carbohydrate-modified (disaccharide) nucleosides are components of tRNA and poly(ADP-ribose) and also participate as second messengers in plants and animals. Base-modified nucleosides contain methylations, acylations, hydroxylations, amino acid and hydrocarbon functionalities, cyclic structure, sulfur or selenium. These modifications are represented in various types of RNA (transport—t, ribosomal—r, matrix—m, small-interfering—si, non-coding—nc RNAs) among all domains of life. They have many important biological implications: RNA splicing, protein biosynthesis, altering RNA structure and functional organization of ribosomes. Many reviews and books were devoted to this theme, but the problems accompanied by the structural diversity of ribonucleosides and their participation in the regulation of macromolecules’ biosynthesis are updated with novel, complex data. In this chapter, general aspects of the structure and functions of modified nucleosides as minor RNA components are given in considering novel scientific achievements. This work highlights essential structural features of various general classes of naturally modified nucleosides and their biosynthetic formation and biological functions. A significant part of this work is devoted to medicinal chemistry. Here we consider the mechanism of action of synthetic nucleosides and drugs on their basis, changing properties of viral RNAs and thus leading to inhibition of viral reproduction and application of nucleoside stable isotope labeled internal standards (SILIS) for analysis of RNA probes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ATP:

Adenosine triphosphate

Tpt1:

TRNA-2′-phosphotransferase 1 (archaeal)

NUDIX hydrolase:

Nucleoside Diphosphates linked to X hydrolase

NudC hydrolase:

Nucleoside Diphosphates in NAD+ Cap hydrolase

snoRNA:

Small nucleolar RNA

TARG1:

Terminal (ADP-ribosyl)hydrolase

MACROD:

Mono(ADP-ribosyl)hydrolase

References

  • Alexeev CS, Kulikova IV, Gavryushov S et al (2018) Quantitative prediction of yield in transglycosylation reaction catalyzed by nucleoside phosphorylases. Adv Synth Catal 360:3090–3096

    Article  CAS  Google Scholar 

  • Bednarek P, Winter J, Hamberger B et al (2004) Induction of 3′-O-β-D-ribofuranosyl adenosine during compatible, but not during incompatible, interactions of Arabidopsis thaliana or Lycopersicon esculentum with Pseudomonas syringae pathovar tomato. Planta 218:668–672

    Article  CAS  PubMed  Google Scholar 

  • Bonnac LF, Mansky LM, Patterson SE (2013) Structure–activity relationships and design of viral mutagens and application to lethal mutagenesis. J Med Chem 56:9403–9414

    Article  CAS  PubMed  Google Scholar 

  • Bruckl T, Globisch D, Wagner M et al (2009) Parallel isotope-based quantification of modified tRNA nucleosides. Angew Chem Int Ed 48:7932–7934

    Article  Google Scholar 

  • Chen P, Shakhnovich EI (2009) Lethal mutagenesis in viruses and bacteria. Genetics 183:639–650

    Article  PubMed  PubMed Central  Google Scholar 

  • Crotty S, Andino R (2002) Implications of high RNA virus mutation rates: lethal mutagenesis and the antiviral drug ribavirin. Microbes Infect 4:1301–1307

    Article  CAS  PubMed  Google Scholar 

  • Crotty S, Maag D, Arnold JJ et al (2000) The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med 6:1375–1379

    Article  CAS  PubMed  Google Scholar 

  • D’Amours D, Desnoyers S, D’Silva I et al (1999) Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 342:249–268

    Article  PubMed  PubMed Central  Google Scholar 

  • Dapp MJ, Clouser CL, Patterson S et al (2009) 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1. J Virol 83:11950–11958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dapp MJ, Patterson SE, Mansky LM (2013) Back to the future: revisiting HIV-1 lethal mutagenesis. Trend Microbiol 2:56–62

    Article  Google Scholar 

  • Domingo E, Holland JJ (1994) Mutation rates and rapid evolution of RNA viruses. In: Morse S (ed) The evolutionary biology of viruses, 1st edn. Raven Press, New York

    Google Scholar 

  • Domingo E, Escarmís C, Sevilla N et al (1996) Basic concepts in RNA virus evolution. FASEB J 10:859–864

    Article  CAS  PubMed  Google Scholar 

  • Drenichev MS, Mikhailov SN (2015) Poly(ADP-ribose)—a unique natural polymer. Structural features, biological role and approaches to the chemical synthesis. Nucleosides, Nucleotides Nucleic Acids 34:258–276

    Article  CAS  PubMed  Google Scholar 

  • Drenichev MS, Mikhailov SN (2016) Poly(ADP-ribose): from chemical synthesis to drug design. Bioorg Med Chem Lett 26:3395–3403

    Article  CAS  PubMed  Google Scholar 

  • Drenichev MS, Oslovsky VE, Mikhailov SN (2016) Cytokinin nucleosides—natural compounds with a unique spectrum of biological activities. Curr Top Med Chem 16:2562–2576

    Article  CAS  PubMed  Google Scholar 

  • Drenichev MS, Bennett M, Novikov RA et al (2019) A role for 3′-O-β-D-ribofuranosyladenosine in altering plant immunity. Phytochem 157:128–134

    Article  CAS  Google Scholar 

  • Efimtseva EV, Kulikova IV, Mikhailov SN (2007) Disaccharide nucleosides and their incorporation into oligonucleotides. Curr Org Chem 11:337–354

    Article  CAS  Google Scholar 

  • Fahrer J, Kranaster R, Altmeyer M et al (2007) Quantitative analysis of the binding affinity of the poly(ADP-ribose) to specific binding proteins as a function of chain length. Nucleic Acids Res 35:e143

    Article  PubMed  PubMed Central  Google Scholar 

  • Ferro AM, Oppenheimer NJ (1978) Structure of a poly(adenosine diphosphoribose) monomer 2′-(5′-phosphoribosyl)-5′-adenosine monophosphate. Proc Natl Acad Sci USA 75:809–813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Földesi A, Trifonova A, Kundu MK et al (2000) The synthesis of deuterionucleosides. Nucleosides, Nucleotides Nucleic Acids 19:1615–1656

    Article  PubMed  Google Scholar 

  • Fox EJ, Loeb LA (2010) Lethal mutagenesis: targeting the mutator phenotype in cancer. Semin Cancer Biol 20:353–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gagne JP, Isabelle M, Lo KS et al (2008) Proteome-wide identification of poly(ADP-ribose) binding proteins and poly(ADP-ribose)-associated protein complexes. Nucleic Acids Res 36:6959–6976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Groslambert J, Prokhorova E, Ahel I (2021) ADP-ribosylation of DNA and RNA. DNA Repair 105:103144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hadj Hassine I, Ben M’hadheb M, Menéndez-Arias L (2022) Lethal mutagenesis of RNA viruses and approved drugs with antiviral mutagenic activity. Viruses 14:841

    Google Scholar 

  • Huang S, Jia A, Song W et al (2022) Identification and receptor mechanism of TIR-catalyzed small molecules in plant immunity. Science 377:eabq3297

    Google Scholar 

  • Jia A, Huang S, Song W et al (2022) TIR-catalyzed ADP-ribosylation reactions produce signaling molecules for plant immunity. BioRxiv. https://doi.org/10.1101/2022.05.02.490369

    Article  PubMed  PubMed Central  Google Scholar 

  • Jiao X, Doamekpor SK, Bird JG et al (2017) 5′ end nicotinamide adenine dinucleotide cap in human cells promotes RNA decay through DXO-mediated deNADding. Cell 168:1015–1027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kistemaker HA, Lameijer LN, Meeuwenoord NJ et al (2015a) Synthesis of well-defined adenosine diphosphate ribose oligomers. Angew Chem 54:4915–4918

    Article  CAS  Google Scholar 

  • Kistemaker HA, Overkleeft HS, van der Marel GA et al (2015b) Branching of poly(ADP-ribose): synthesis of the core motif. Org Lett 17:4328–4331

    Article  CAS  PubMed  Google Scholar 

  • Kolitz SE, Lorsch JR (2010) Eukaryotic initiator tRNA: finely tuned and ready for action. FEBS Lett 584:396–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kulikova IV, Muradova DA, Drenichev MS et al (2015) Stereoselective synthesis of 2′-O-α-D-ribofuranosyluridine, a structural fragment of Hellecaucaside A. Chem Nat Comp 51:256–260

    Article  CAS  Google Scholar 

  • Liu Q, Kistemaker HA, Overkleeft HS et al (2017) Synthesis of ribosyl-ribosyl-adenosine-5′,5″,5‴(triphosphate)−the naturally occurring branched fragment of poly(ADP ribose). Chem Commun 53:10255–10258

    Article  CAS  Google Scholar 

  • Manik MK, Shi Y, Li S et al (2022) Cyclic ADP ribose isomers: production, chemical structures, and immune signaling. Science 377:eadc8969

    Google Scholar 

  • Mathews CK, Van Holde KE (1996) Biochemistry. Benjamin Cummings PC, San Francisco

    Google Scholar 

  • McCown PJ, Ruszkowska A, Kunkler CN et al (2020) Naturally occurring modified ribonucleosides. WIREs RNA 11:e1595

    Article  CAS  PubMed  Google Scholar 

  • Messner S, Altmeyer M, Zhao H et al (2010) PARP-1 ADP-ribosylates lysine residues of the core histone tails. Nucleic Acid Res 38:6350–6362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meyer R, Meyer-Ficca M, Jacobsen E, Jacobsen M (2006) Enzymes in poly(ADP-Ribose) metabolism. In: Burkle A (ed) Poly(ADP-Ribosyl)ation. Molecular biology intelligence unit. Springer Science+Business Media Inc, New York

    Google Scholar 

  • Minaga T, Kun E (1983) Probable helical conformation of poly(ADP-ribose). J Biol Chem 258:5726–5730

    Article  CAS  PubMed  Google Scholar 

  • Miwa M, Ishihara M, Takishima S et al (1981) The branching and linear portions of poly(adenosine diphosphate ribose) have the same alpha (1 leads to 2) ribose-ribose linkage. J Biol Chem 256:2916–2921

    Article  CAS  PubMed  Google Scholar 

  • Moreau C, Ashamu GA, Bailey VC et al (2011) Synthesis of cyclic adenosine 5′-diphosphate ribose analogues: a C2′endo/syn “southern” ribose conformation underlies activity at the sea urchin cADPR receptor. Org Biomol Chem 9:278–290

    Article  CAS  PubMed  Google Scholar 

  • Munir A, Banerjee A, Shuman S (2018) NAD+-dependent synthesis of a 5-phospho-ADP-ribosylated RNA/DNA cap by RNA 2-phosphotransferase Tpt1. Nucleic Acids Res 46:9617–9624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Munnur D, Bartlett E, Mikolčević P et al (2019) Reversible ADP-ribosylation of RNA. Nucleic Acid Res 47:5658–5669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pearson D, Hienzsch A, Wagner M et al (2011) LC-MS based quantification of 2-O-ribosylated nucleosides Ar(p) and Gr(p) in tRNA. Chem Commun 47:5196–5198

    Article  CAS  Google Scholar 

  • Penzo M, Guerrieri AN, Zacchini F et al (2017) RNA pseudouridylation in physiology and medicine: For better and for worse. Genes 8:301

    Article  PubMed  PubMed Central  Google Scholar 

  • Perales C, Martín V, Domingo E (2011) Lethal mutagenesis of viruses. Curr Opin Virol 1:419–422

    Article  CAS  PubMed  Google Scholar 

  • Popova AM, Williamson JR (2014) Quantitative analysis of rRNA modifications using stable isotope labeling and mass spectrometry. J Am Chem Soc 136:2058–2069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robson F, Khan KS, Le TK et al (2020) Coronavirus RNA proofreading: molecular basis and therapeutic targeting. Mol Cell 79:710–727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schultheisz HL, Szymczyna BR, Williamson JR (2009) Enzymatic synthesis and structural characterization of 13C, 15N-Poly(ADP-ribose). J Am Chem Soc 131:14571–14578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schultz SK, Kothe U (2021) Partially modified tRNAs for the study of tRNA maturation and function. In: Jackman JE (ed) Methods in enzymology, 1st edn. Academic Press, New York

    Google Scholar 

  • Steinhauer DA, Domingo E, Holland JJ (1992) Lack of evidence for proofreading mechanisms associated with an RNA virus polymerase. Gene 122:281–288

    Article  CAS  PubMed  Google Scholar 

  • Sylla B, Gauthier C, Legault J et al (2014) Isolation of a new disaccharide nucleoside from Helleborus caucasicus: structure elucidation and total synthesis of hellecaucaside A and its β-anomer. Carbohydr Res 398:80–89

    Article  CAS  PubMed  Google Scholar 

  • Tong J, Flavell RA, Li HB (2018) RNA m6A modification and its function in diseases. Front Med 12:481–489

    Article  PubMed  Google Scholar 

  • Vorbruggen H, Ruh-Pohlenz C (2001) Handbook of nucleoside synthesis. Wiley, New York

    Google Scholar 

  • Walters RW, Matheny T, Mizoue LS et al (2017) Identification of NAD+ capped mRNAs in Saccharomyces cerevisiae. PNAS 114:480–485

    Article  CAS  PubMed  Google Scholar 

  • Watt JM, Thomas MP, Potter BV (2018) Synthetic cADPR analogues may form only one of two possible conformational diastereoisomers. Sci Rep 8:15268

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang HZ, Pan MY, Jiang DW et al (2011) Synthesis of Janus type nucleoside analogues and their preliminary bioactivity. Org Biomol Chem 9:1516–1522

    Article  CAS  PubMed  Google Scholar 

  • Zenchenko AA, Drenichev MS, Il’icheva IA et al (2021) Antiviral and antimicrobial nucleoside derivatives: structural features and mechanisms of action. Rus J Mol Biol 55:785–811

    Google Scholar 

  • Zhao Y, He G, Huang W (2021) A novel model of molnupiravir against SARS-CoV-2 replication: accumulated RNA mutations to induce error catastrophe. Signal Transduct Target Ther 6:1–3

    Google Scholar 

Download references

Acknowledgements

This work was funded by Russian Science Foundation, project number 21-14-00346.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mikhail S. Drenichev .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Drenichev, M.S., Zenchenko, A.A., Alexeev, C.S. (2023). Modified Nucleosides as RNA Components. Structure, Biological Role and Drug Design. In: Barciszewski, J. (eds) RNA Structure and Function. RNA Technologies, vol 14. Springer, Cham. https://doi.org/10.1007/978-3-031-36390-0_23

Download citation

Publish with us

Policies and ethics