Aptamers are nucleic acid molecules that mimic antibodies by folding into complex 3D shapes that bind to specific targets. Although some aptamers exist naturally as the ligand-binding elements of riboswitches, most are generated in vitro and can be tailored for a specific target. Relative to antibodies, aptamers benefit from their ease of generation, low production cost, low batch-to-batch variability, reversible folding properties and low immunogenicity. However, the true value of aptamers lies in the simplicity by which these molecules can be engineered into sensors, actuators and other devices that are often central to emerging technologies. This Review examines changing trends in aptamer technology by analysing the first quarter century of aptamer data that is available in the scientific literature (1990–2015). We highlight specific examples that showcase the use of aptamers in key applications, discuss challenges that have impeded the success of aptamers in practical applications, provide suggestions for choosing chemical modifications that can lead to enhanced activity or stability, and propose standards for the characterization of aptamers in the scientific literature. Aptamers are nucleic acid molecules that can be evolved to bind to specific molecular targets and have found applications in technologies such as sensors and actuators. This Review provides a critical analysis of the first 25 years of aptamer research.

Analysis of aptamer discovery and technology

The past decade has witnessed ongoing progress in precision medicine to improve human health. As an emerging diagnostic technique, liquid biopsy can provide real-time, comprehensive, dynamic physiological and pathological information in a noninvasive manner, opening a new window for precision medicine. Liquid biopsy depends on the sensitive and reliable detection of circulating targets (e.g., cells, extracellular vesicles, proteins, microRNAs) from body fluids, the performance of which is largely governed by recognition ligands. Aptamers are single-stranded functional oligonucleotides, capable of folding into unique tertiary structures to bind to their targets with superior specificity and affinity. Their mature evolution procedure, facile modification, and affinity regulation, as well as versatile structural design and engineering, make aptamers ideal recognition ligands for liquid biopsy. In this review, we present a broad overview of aptamer-based liquid biopsy techniques for precision medicine. We begin with recent advances in aptamer selection, followed by a summary of state-of-the-art strategies for multivalent aptamer assembly and aptamer interface modification. We will further describe aptamer-based micro-/nanoisolation platforms, aptamer-enabled release methods, and aptamer-assisted signal amplification and detection strategies. Finally, we present our perspectives regarding the opportunities and challenges of aptamer-based liquid biopsy for precision medicine.

Aptamer-Based Detection of Circulating Targets for Precision Medicine.

Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.

Selective small-molecule inhibition of an RNA structural element

Next-generation sequencing (NGS) is the method of choice when large numbers of sequences have to be obtained. While the technique is widely applied, varying error rates have been observed. We analysed millions of reads obtained after sequencing of one single sequence on an Illumina sequencer. According to our analysis, the index-PCR for sample preparation has no effect on the observed error rate, even though PCR is traditionally seen as one of the major contributors to enhanced error rates in NGS. In addition, we observed very persistent pre-phasing effects although the base calling software corrects for these. Removal of shortened sequences abolished these effects and allowed analysis of the actual mutations. The average error rate determined was 0.24 ± 0.06% per base and the percentage of mutated sequences was found to be 6.4 ± 1.24%. Constant regions at the 5′- and 3′-end, e.g., primer binding sites used in in vitro selection procedures seem to have no effect on mutation rates and re-sequencing of samples obtains very reproducible results. As phasing effects and other sequencing problems vary between equipment and individual setups, we recommend evaluation of error rates and types to all NGS-users to improve the quality and analysis of NGS data.

Systematic evaluation of error rates and causes in short samples in next-generation sequencing.

In this review, we introduce two kinds of bio-related nanoarchitectonics, DNA nanoarchitectonics and cell-macromolecular nanoarchitectonics, both of which are basically controlled by chemical strategies. The former DNA-based approach would represent the precise nature of the nanoarchitectonics based on the strict or “digital” molecular recognition between nucleic bases. This part includes functionalization of single DNAs by chemical means, modification of the main-chain or side-chain bases to achieve stronger DNA binding, DNA aptamers and DNAzymes. It also includes programmable assemblies of DNAs (DNA Origami) and their applications for delivery of drugs to target sites in vivo, sensing in vivo, and selective labeling of biomaterials in cells and in animals. In contrast to the digital molecular recognition between nucleic bases, cell membrane assemblies and their interaction with macromolecules are achieved through rather generic and “analog” interactions such as hydrophobic effects and electrostatic forc...

Chemistry Can Make Strict and Fuzzy Controls for Bio-Systems: DNA Nanoarchitectonics and Cell-Macromolecular Nanoarchitectonics

A novel and versatile method has been developed for modular expansion of the chemical space of nucleic acid libraries, thus enabling the generation of nucleobase-modified aptamers with unprecedented recognition properties. Reintroduction of the modification after enzymatic replication gives broad access to many chemical modifications. This wide applicability, which is not limited to a single modification, will rapidly advance the application of in vitro selection approaches beyond what is currently feasible and enable the generation of aptamers to many targets that have so far not been addressable.

A Versatile Approach Towards Nucleobase‐Modified Aptamers

The rise of antimicrobial resistance in human pathogenic bacteria has increased the necessity for the discovery of novel, yet unexplored antibacterial drug targets. Riboswitches, which are embedded in untranslated regions of bacterial messenger RNA (mRNA), represent such an interesting target structure. These RNA elements regulate gene expression upon binding to natural metabolites, second messengers, and inorganic ions, such as fluoride with high affinity and in a highly discriminative manner. Recently, efforts have been directed toward the identification of artificial riboswitch activators by establishing high-throughput screening assays, fragment-based screening, and structure-guided ligand design approaches. Emphasis in this review is placed on the special requirements and synthesis of new potential antibiotic drugs that target riboswitches in which dissimilarity is an important aspect in the design of potential lead compounds.

Dis)similar Analogues of Riboswitch Metabolites as Antibacterial Lead Compounds.

The ever-growing number of pathogenic bacteria resistant to treatment with antibiotics call for the development of novel compounds with as-yet unexplored modes of action. Here, we demonstrate the in vivo antibacterial activity of carba-α-d-glucosamine (CGlcN). In this mode of action study, we provide evidence that CGlcN-mediated growth inhibition is due to glmS ribozyme activation, and we demonstrate that CGlcN hijacks an endogenous activation pathway, hence utilizing a prodrug mechanism. This is the first report describing antibacterial activity mediated by activating the self-cleaving properties of a ribozyme. Our results open the path towards a compound class with an entirely novel and distinct molecular mechanism.

Activation of the glmS Ribozyme Confers Bacterial Growth Inhibition.

The glmS ribozyme is a bacterial gene-regulating riboswitch that controls cell wall synthesis, depending on glucosamine-6-phosphate as a cofactor. Due to the presence of this ribozyme in several human pathogen bacteria (e.g., MRSA, VRSA), the glmS ribozyme represents an attractive target for the development of artificial cofactors. The substitution of the ring oxygen in carbohydrates by functionalized methylene groups leads to a new generation of glycomimetics that exploits distinct interaction possibilities with their target structure in biological systems. Herein, we describe the synthesis of mono-fluoro-modified carba variants of α-d-glucosamine and β-l-idosamine. (5aR)-Fluoro-carba-α-d-glucosamine-6-phosphate is a synthetic mimic of the natural ligand of the glmS ribozyme and is capable of effectively addressing its unique self-cleavage mechanism. However, in contrast to what was expected, the activity is significantly decreased compared to its non-fluorinated analog. By combining self-cleavage assays with the Bacillus subtilis and Staphylococcus aureus glmS ribozyme and molecular docking studies, we provide a structure-activity relationship for fluorinated carba-sugars.

Fluoro-Carba-Sugars are Glycomimetic Activators of the glmS Ribozyme.

Wir beschreiben eine neue und vielseitige Methode, um die chemische Diversitat von Nucleinsaurebibliotheken modular zu erweitern. Dies ermoglicht den Zugang zu Nucleobasen-modifizierten Aptameren mit einer bisher unerreicht hohen Affinitat und Spezifitat fur ihre Zielstrukturen. Die Wiedereinfuhrung der Modifikation nach der enzymatischen Replikation gewahrt dabei einen eleganten Zugang zu einer Vielzahl von chemischen Gruppen. Die breite Anwendbarkeit, die sich nicht auf eine einzige Modifikation beschrankt, wird in Zukunft In-vitro-Selektionsprozesse rasant voranbringen und weitere Aptamere fur viele bis dato nicht adressierbare Zielstrukturen generieren.

Ein universeller Zugang zu Nucleobasen‐modifizierten Aptameren

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