biomedicines Review Triazole-Modified Nucleic Acids for the Application in Bioorganic and Medicinal Chemistry Dagmara Baraniak * and Jerzy Boryski Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-61-852-8503 Abstract: This review covers studies which exploit triazole-modified nucleic acids in the range of chemistry and biology to medicine. The 1,2,3-triazole unit, which is obtained via click chemistry approach, shows valuable and unique properties. For example, it does not occur in nature, constitutes an additional pharmacophore with attractive properties being resistant to hydrolysis and other reactions at physiological pH, exhibits biological activity (i.e., antibacterial, antitumor, and antiviral), and can be considered as a rigid mimetic of amide linkage. Herein, it is presented a whole area of useful artificial compounds, from the clickable monomers and dimers to modified oligonucleotides, in the field of nucleic acids sciences. Such modifications of internucleotide linkages are designed to increase the hybridization binding affinity toward native DNA or RNA, to enhance resistance to nucleases, and to improve ability to penetrate cell membranes. The insertion of an artificial backbone is used for understanding effects of chemically modified oligonucleotides, and their potential usefulness in therapeutic applications. We describe the state-of-the-art knowledge on their implications for synthetic genes and other large modified DNA and RNA constructs including non-coding RNAs. Citation: Baraniak, D.; Boryski, J. Keywords: click chemistry; 1,2,3-triazoles; backbone modifications; triazole-linkage; clickable nucle- Triazole-Modified Nucleic Acids for osides and nucleotides; triazole-modified oligonucleotides; (TL)DNA; (TL)RNA; (TL)LNA; (TL)BNA; the Application in Bioorganic and (TL)PNA; (TL)quadruplexes; non-coding RNA; synthetic genes Medicinal Chemistry. Biomedicines 2021, 9, 628. https://doi.org/ 10.3390/biomedicines9060628 Academic Editor: Shaker A. Mousa 1. Introduction 1.1. A Brief Introduction to DNA and RNA World Received: 29 April 2021 The natural nucleic acids, DNA and RNA, are exquisitely suited to store and propagate Accepted: 26 May 2021 genetic information [1,2]. Nucleic acids are unique among biopolymers, because of their Published: 31 May 2021 high-water solubility together with denaturing and refolding abilities [3]. DNA is an enormously intricate yet simple molecule. Its beauty is hidden in a stable double-stranded Publisher’s Note: MDPI stays neutral helix, that is guarded in the cell nucleus for storing genetic material and because of with regard to jurisdictional claims in its self-replication abilities. In turn, remarkable RNA most often is a single-stranded published maps and institutional affil- molecule, but it could adopt different structures and functions in the cell. It can mediate iations. the heritable storage, recognize specific targets (aptamers), and even catalyze reactions [4]. RNA molecules are generally less stable and are quickly degraded by intracellular enzymes, hence the great need for chemical modifications. Thus, understanding and cognition of their capabilities such as direct protein synthesis and modulation of gene expression allow Copyright: © 2021 by the authors. us to understand how life works [5]. Likewise, it is worth to notice that in all DNA and Licensee MDPI, Basel, Switzerland. RNA technologies the Watson–Crick base pairs are responsible for the information content This article is an open access article of all living systems [6–9]. Nowadays, RNA has become a focus of attention because it distributed under the terms and turned out that various RNAs are valuable tools in molecular biology and medicine. These conditions of the Creative Commons molecules, including all classes of ncRNAs, are used in the design and development of Attribution (CC BY) license (https:// drugs for fighting cancers, viruses, and other diseases at the nucleic acids level. creativecommons.org/licenses/by/ 4.0/). Biomedicines 2021, 9, 628. https://doi.org/10.3390/biomedicines9060628 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 628 2 of 34 Biomedicines 2021, 9, 628 2 of 35 development of drugs for fighting cancers, viruses, and other diseases at the nucleic acids level. 1.2.1.2. Non-CodingNon-Coding RNARNA InIn the the world world of of science, science, the the key key role role for for regulating regulating life life processes processes is ascribed is ascribed to proteins. to pro- 0 Sinceteins. the Since genetic the genetic information information about them about isencoded them is inencoded 2 -deoxyribonucleic in 2′-deoxyribonucleic acid (DNA), acid it found(DNA), itself it found on the itself podium on the of podium fame. An of unappreciatedfame. An unappreciated ribonucleic ribonucleic acid (RNA) acid stood (RNA) in itsstood shade—a in its shade—a silent hero silent with hero many with faces. many From faces. the From central the dogma central of dogma molecular of molecular biology, itbiology, can be seenit can that be seen the flow that ofthe genetic flow of information, genetic information, which takes which place takes from place DNA from through DNA RNAthrough to protein, RNA to involves protein, ainvolves molecule a ofmolecu RNA,le and of RNA, exactly and the exactly messenger the messenger RNA (mRNA). RNA It(mRNA). follows thatIt follows the mRNA that the molecule mRNA ismolecule coding RNAis coding in transcription, RNA in transcription, because it because rewrites it informationrewrites information from DNA from about DNA proteins. about proteins. A further A stagefurther is stage yet involved: is yet involved: ribosomal ribosomal RNA (rRNA)RNA (rRNA) and transfer and transfer RNA (tRNA). RNA (tRNA). 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We know [10,11]. that We the know proteins-coding that the proteins-coding genes constitute genes only constitute 2–3% of theonly entire 2–3% human of the entire genome human and thegenome remaining and the 97–98% remaining (wrongly 97–98% called (wrongly “junk” called DNA) “junk” [12], theyDNA) are [12], sequences they are responsible sequences responsible for the formation for the offormation a numerous of a numerous and diverse and group diverse of ncRNA molecules (Figure1)[13,14]. group of ncRNA molecules (Figure 1) [13,14]. RNA Transcript Coding RNA Non-coding RNA mRNA ncRNA long ncRNA small ncRNA 200 nt 200 nt linear: rRNA, asRNA, tRNA, snRNA, snoRNA, ceRNA, eRNA, pRNA, sdRNA, rasiRNA, scaRNA gsRNA, lincRNA, lncRNA, NAT miRNA, siRNA, piRNA, circular: circRNA tiRNA, stRNA, endo-siRNA FigureFigure 1.1.Diagram Diagram presentingpresenting thethe RNARNA world. world. MoreMore thanthan 40%40% ofof thethe humanhuman genomegenome isis transcribedtranscribed asas ncRNA,ncRNA, whatwhat causescauses thatthat chemicalchemical diversity diversity in in RNAs RNAs is is huge.huge. TheThe above-mentionedabove-mentioned rRNA rRNA and and tRNA tRNA are are molecules molecules thatthat occur occur in in all all cells, cells, because because they they control control the the basic basic processes, processes, therefore therefore minor minor disturbances disturb- inances the functionin the function can cause can seriouscause serious diseases. diseas Thees. fact The is fact that is the that RNA the worldRNA world is rich—it is rich— can beit can more beindependent, more independent, which which is evidenced is evidenced in the in discovery the discovery of ribozymes, of ribozymes, and thatand hasthat becomehas become a milestone a milestone in molecular in molecular biology biology [15 [15].]. It hasIt has been been proved proved that that RNA RNA molecules molecules areare capablecapable ofof carryingcarrying outout thethe reaction—editing reaction—editingmRNA, mRNA,modifying modifyingimmature immaturetRNA, tRNA,or or participatingparticipating inin thethe synthesissynthesis ofof ribosomes.ribosomes. ButBut theythey cancan alsoalso actact asas diagnosticdiagnostic tools,tools, e.g.e.g.,, smallsmall nuclear nuclear RNA RNA (snRNA) (snRNA) or or small small nucleolar nucleolar RNA RNA (snoRNA) (snoRNA) [16 ,[16,17].17]. In turn,In turn, regulatory regula- microRNAstory microRNAs (miRNAs) (miRNAs) control control gene expression, gene expression, and are and also are involved also involved in brain in development brain devel- andopment nerve and cell nerve specialization cell specialization [18]. Disorders [18]. Di ofsorders these molecules of these molecules lead to the lead development to the devel- of tumors,opment including of tumors, brain including gliomas brain [19,20 gliomas], gastric [19,20], cancer [gastric21], or breastcancer cancer[21], or [22 breast]. Therefore, cancer research[22]. Therefore, is ongoing research to develop is ongoing anti-cancer to deve strategieslop anti-cancer based onstrategies miRNAs based [23], one.g. miRNAs, prepa- ration[23], e.g. of, synthetic preparation oligonucleotides of synthetic oligonucleotides complementary complementary