Uptake mechanisms of cell-internalizing nucleic acid aptamers for applications as pharmacological agents

Alamudi, Samira Husen; Kimoto, Michiko; Hirao, Ichiro

doi:10.1039/d1md00199j

Cited by 10 publications

(13 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This observation can be attributed to the competitive internalization of PS-ApTCs and PS-AS1411 through NCL-mediated process. 52 Notably, the degradation ability of PS-ApTCs was not significantly affected with a shorter PEG chain (Figure S10). Moreover, the degradation of cytoplasmic NCL by PS-ApTCs could be completely blocked by the proteasome inhibitor MG132 (Figure 2C).…”

Section: Rationalmentioning

confidence: 98%

Cooperatively Designed Aptamer-PROTACs for Spatioselective Degradation of Nucleocytoplasmic Shuttling Protein for Enhanced Combinational Therapy

Liu

Chen

et al. 2022

Preprint

View full text Add to dashboard Cite

Nucleocytoplasmic shuttling proteins (NSPs) has emerged as a promising class of therapeutic targets for many diseases including cancer. However, most reported NSPs-based therapies largely rely on small molecule inhibitors with limited efficacy and off-target effects. Proteolysis targeting chimera (PROTAC) represents a revolutionary inhibitory modality for targeted protein degradation with many advantages, including substoichiometric catalytic activity, improved selectivity, and high efficacy. However, the majority of reported PROTACs so far are still limited to the degradation of cytoplasmic proteins and lack of tumor-specific targeting. To realize the full potential of the PROTAC technology and broaden its applications for the degradation of NSPs, we herein report a conceptual approach for the design of a new archetype of PROTAC (denoted as PS-ApTCs) by introducing phosphorothioate-modified AS1411 aptamer to a ligand of the CRBN E3 ligase, realizing tumor-targeting and spatioselective degradation with improved efficacy. We have demonstrated that PS-ApTCs is capable of effectively degrading nucleolin in target cell membrane and cytoplasm but not in the nucleus, in a CRBN- and proteasome-dependent manner. In addition, PS-ApTCs exhibits superior antiproliferation, pro-apoptotic, and cell cycle arrest potencies. Importantly, we demonstrate for the first time that combination of PS-ApTCs-mediated nucleolin degradation with aptamer-drug conjugates-based chemotherapy can enable an AND-gated synergistic effect on tumor inhibition. Collectively, our results suggest that PS-ApTCs possess the ability to expand the PROTACs toolbox to even wider range of targets in subcellular localization and accelerate the discovery of new combinational therapeutic approaches.

show abstract

Section: Rationalmentioning

confidence: 98%

Cooperatively Designed Aptamer-PROTACs for Spatioselective Degradation of Nucleocytoplasmic Shuttling Protein for Enhanced Combinational Therapy

Liu

Chen

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

Section: Molecular Designs Of Novel Aptamersmentioning

confidence: 99%

“…In another genetic alphabet expansion approach developed by Benner (Figure 5c), the hydrogen bonding pattern of nucleobases is modified so that the resulting analogues specifically form specific hydrogen bonding interactions. [49][50][51] These unnatural base pairs are fully orthogonal to the canonical, Watson-Crick base pairs. This versatile method, coined artificially expanded genetic information systems (AEGIS), has been exploited to generate highly potent modified aptamers against cell cancer lines [22,52,53] as well as protein [54] targets.…”

Section: Genetic Alphabet Expansionmentioning

confidence: 99%

Chemical Modifications for a Next Generation of Nucleic Acid Aptamers

et al. 2022

View full text Add to dashboard Cite

In the past three decades, in vitro systematic evolution of ligands by exponential enrichment (SELEX) has yielded many aptamers for translational applications in both research and clinical settings. Despite their promise as an alternative to antibodies, the low success rate of SELEX (∼30 %) has been a major bottleneck that hampers the further development of aptamers. One hurdle is the lack of chemical diversity in nucleic acids. To address this, the aptamer chemical repertoire has been extended by introducing exotic chemical groups, which provide novel binding functionalities. This review will focus on how modified aptamers can be selected and evolved, with illustration of some successful examples. In particular, unique chemistries are exemplified. Various strategies of incorporating modified building blocks into the standard SELEX protocol are highlighted, with a comparison of the differences between pre‐SELEX and post‐SELEX modifications. Nucleic acid aptamers with extended functionality evolved from non‐natural chemistries will open up new vistas for function and application of nucleic acids.

show abstract

“…The SELEX process can be conducted to target pathogenic microorganisms such as bacteria, viruses, and protozoa for the diagnosis of infectious diseases caused by pathogens [ 14 ]. Aptamers generated through this process are also targeting mammalian cell lines [ 15 ]. Aptamers identified from SELEX can target specific surface molecules on pathogens or cell lines with high affinity and inhibit the mechanism of disease-causing agents.…”

Section: Aptamers Against Pathogenic Microorganisms and Mammalian Cellsmentioning

confidence: 99%

Advances in Aptamer-Based Biosensors and Cell-Internalizing SELEX Technology for Diagnostic and Therapeutic Application

et al. 2022

View full text Add to dashboard Cite

Aptamers are a group of synthetic single-stranded nucleic acids. They are generated from a random library of single-stranded DNA or RNA by a technology named systematic evolution of ligands by exponential enrichment (SELEX). SELEX is a repetitive process to select and identify suitable aptamers that show high affinity and specificity towards target cells. Great strides have been achieved in the design, construction, and use of aptamers up to this point. However, only a small number of aptamer-based applications have achieved widespread commercial and clinical acceptance. Additionally, finding more effective ways to acquire aptamers with high affinity remains a challenge. Therefore, it is crucial to thoroughly examine the existing dearth and advancement in aptamer-related technologies. This review focuses on aptamers that are generated by SELEX to detect pathogenic microorganisms and mammalian cells, as well as in cell-internalizing SELEX for diagnostic and therapeutic purposes. The development of novel aptamer-based biosensors using optical and electrical methods for microbial detection is reported. The applications and limitations of aptamers are also discussed.

show abstract

Uptake mechanisms of cell-internalizing nucleic acid aptamers for applications as pharmacological agents

Abstract: Nucleic acid aptamers, also regarded as chemical antibodies, manifest potentials for targeted therapeutic and delivery agents since they possess unique advantages over antibodies. Generated by an iterative in vitro selection...

Cited by 10 publications

References 103 publications

Cooperatively Designed Aptamer-PROTACs for Spatioselective Degradation of Nucleocytoplasmic Shuttling Protein for Enhanced Combinational Therapy

Cooperatively Designed Aptamer-PROTACs for Spatioselective Degradation of Nucleocytoplasmic Shuttling Protein for Enhanced Combinational Therapy

Chemical Modifications for a Next Generation of Nucleic Acid Aptamers

Advances in Aptamer-Based Biosensors and Cell-Internalizing SELEX Technology for Diagnostic and Therapeutic Application

Contact Info

Product

Resources

About