**2. From enzyme to DNAzyme**

## **2.1. From enzyme to ribozyme**

Long regarded as the only biomolecules able to catalyze chemical reactions, proteins are not the exclusive edifices playing this pivotal role in biological systems. Indeed, at the beginning of the 1980s, it was discovered that RNA (for *ribonucleic acids*) share also this property and are involved in numerous biological process.[1, 2] Some of the most representative examples are certainly the RNase P catalyzing transfer RNA (or tRNA) maturation [17], the riboregulators (also termed riboswitches) incorporated in certain messenger RNA (or mRNA), and control‐ ling transcription or translation *in cellulo*.[18, 19] Active site of the ribosomes, composed of ribosomal RNA (or rRNA) and catalyzing the protein synthesis in the cytoplasm, also has to be highlighted.[20] This ability of RNA to catalyze an enzymatic reaction was termed "ribo‐ zyme," obtained by contracting the words "ribonucleic acids" and "enzyme." This fantastic biological and chemical breakthrough was honored in 1989 by the Nobel Prize in Chemistry, attributed to the two pioneers of this field: Sidney Altman and Thomas R. Cech.[3, 4] The potential of these ribozymes quickly drew the scientific community's attention which devel‐ oped the very first artificial ones in 1990.[21] The RNA sequences were first designed to catalyze single-strand RNA cleavage and then for RNA ligation, porphyrin metalation, or more classic organic chemical reactions like Diels–Alder and Michael reactions.[22]

## **2.2. From ribozyme to DNAzyme**

they play a pivotal role in living systems. All along the years, nature develops strategies to catalyze biochemical reactions. The most representative catalysts are undoubtedly the enzymes, but they are not the only ones. Interestingly, ribonucleic acids (also known as RNA) are also able to play this role and to catalyze key reactions, like in the active site of the ribosome during the translation of messenger RNA (mRNA). Besides, it is strongly supposed that the origins of the prebiotic life were based on the use of RNA as both the carrier of the genetic information, and a catalyst: RNA was a self-sufficing molecule. This theory was termed "RNA

Inspired by the role of RNA as a catalyst, chemists developed new catalytic systems based on deoxyribonucleic acids, also termed DNA.[7, 8] DNA offers more advantages, like its better stability compared to the RNA equivalent.[9] These aspects are developed in section 2 of this

Among all the DNA structures used as catalysts (*e.g*., canonical duplex structures or nonca‐ nonical triplexes, etc.), author would like to highlight the reader on the G-quadruplex struc‐ tures.[10] These noncanonical edifices, composed of a stacking of native G-quartets, are introduced in section 3. This presentation is followed by the story of the discovery of Gquadruplexes as catalysts, and then, by a rationalization of how this chemical mechanism works, and how chemists can modulate experimental conditions to obtain the efficiency desired. To complete the presentation, the large range of applications of these noncanonical structures is commented on and shows how versatile and effective quadruplex DNA are.

Based on the observation that the catalytic activity of G-quadruplex is mainly due to the presence of native G-quartets,[11] several groups designed new molecules able to form a synthetic G-quartet. The most representative examples are TASQ (for *template-assembled synthetic G-quartet*), [12–16] composed of four guanines grafted on a template, and able to selfassemble into an intramolecular G-quartet. In section 4 of this chapter, the concept of TASQ is first clarified and then their catalytic activity is specified. Finally, the very first applications proposed in the literature are described, and pave the way to the use of synthetic molecules

Long regarded as the only biomolecules able to catalyze chemical reactions, proteins are not the exclusive edifices playing this pivotal role in biological systems. Indeed, at the beginning of the 1980s, it was discovered that RNA (for *ribonucleic acids*) share also this property and are involved in numerous biological process.[1, 2] Some of the most representative examples are certainly the RNase P catalyzing transfer RNA (or tRNA) maturation [17], the riboregulators (also termed riboswitches) incorporated in certain messenger RNA (or mRNA), and control‐ ling transcription or translation *in cellulo*.[18, 19] Active site of the ribosomes, composed of ribosomal RNA (or rRNA) and catalyzing the protein synthesis in the cytoplasm, also has to be highlighted.[20] This ability of RNA to catalyze an enzymatic reaction was termed "ribo‐

world."[1–6]

chapter.

to mimic natural enzymes, like peroxidases.

448 Advanced Catalytic Materials - Photocatalysis and Other Current Trends

**2. From enzyme to DNAzyme**

**2.1. From enzyme to ribozyme**

Interestingly, not any natural catalytic deoxyribonucleic acids (or DNA) has been found as yet in nature. However, their higher chemical stability compared to RNA and proteins makes DNA catalysts of choice for chemists who want to develop innovative applications in a larger range of experimental conditions. Indeed, the DNA stability against heat treatment and hydrolysis is evaluated at 1.000 and 100.000 times higher than for RNA and proteins, respectively. [9] Furthermore, obtaining specific designed DNA sequences is increasingly easy, thanks to the automated DNA synthesizers for both academic laboratories and the industry. In parallel, several companies are specialized in the custom DNA synthesis, and offer the opportunity for everybody to work now with DNA catalysts. Other advantages of using DNA as a catalyst can be highlighted here, like the possibility to functionalize it (*e.g.*, fluorescent probes or specific other moieties), to graft it on a solid support (*e.g*., polymers, gold surface), and on top of that, the virtually unlimited number of catalysts that may be obtained by modulating both the number and the nature of the nucleotides.[7, 23, 24] Thus, chemists can design the specific sequence meeting their requests in term of application and efficiency.

It was not until 1994 that the first instance of an artificial catalytic DNA, termed "deoxyribo‐ zyme" (by analogy with the ribozymes) or most widely named "DNAzyme," was published. [25] Since then, plenty of applications has been developed, from the most original to the most complex ones, using different kinds of DNA structures. As a matter of fact, DNA is a highly versatile molecule that can self-assemble into several tridimensional organizations, depending of the sequences and conditions.[7, 23, 24] The most familiar form is undoubtedly the doublehelix (also termed duplex) DNA form, used as a DNAzyme for enantioselective Diels–Alder and Friedel–Craft reactions.[7, 22] Nevertheless, other noncanonical DNA structures were also studied for their ability to catalyze chemical reactions. The two most representative structures are the triplex and the G-quadruplex DNA forms, with a clear predominance for the latter ones, which constitute the next section of this book chapter.[23, 24]
