Systematic Combination of Oligonucleotides and Synthetic Polymers for Advanced Therapeutic Applications

Han, Moohyun; Beon, Jiyun; Lee, Ju Young; Oh, Seung Soo

doi:10.1007/s13233-021-9093-5

Cited by 7 publications

(6 citation statements)

References 196 publications

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“…Original transmembrane receptors have critical drawbacks as viral neutralizers; the lipophilic membrane proteins are insoluble and could not be readily administered in our bodies ( 11 ), and their massive size can cause steric hindrance in covering the surface of viruses, such as coronaviruses with high-density surficial spike proteins ( 45 ). On the other hand, highly soluble and modifiable nucleic acids with no immunogenicity have been FDA-approved for intravenous drugs ( 33 , 46 ), and the molecular weight of R7-02, the strongest RBD-binding hybrid ligand with the improved nuclease resistance, is just 20 kDa, which is roughly 18% of native hACE2 receptors. Moreover, in choosing the hotspot peptide from hACE2, we intentionally included positively charged and hydrophobic amino acids, i.e., lysine and arginine for the positive charges and leucine and phenylalanine for hydrophobic interactions, to expand the chemical and structural diversity of ligand candidates, which are mainly constituted by hydrophilic and negatively charged nucleic acids.…”

Section: Discussionmentioning

confidence: 99%

De novo selected hACE2 mimics that integrate hotspot peptides with aptameric scaffolds for binding tolerance of SARS-CoV-2 variants

et al. 2022

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The frequent occurrence of viral variants is a critical problem in developing antiviral prophylaxis and therapy; along with stronger recognition of host cell receptors, the variants evade the immune system–based vaccines and neutralizing agents more easily. In this work, we focus on enhanced receptor binding of viral variants and demonstrate generation of receptor-mimicking synthetic reagents, capable of strongly interacting with viruses and their variants. The hotspot interaction of viruses with receptor-derived short peptides is maximized by aptamer-like scaffolds, the compact and stable architectures of which can be in vitro selected from a myriad of the hotspot peptide-coupled random nucleic acids. We successfully created the human angiotensin-converting enzyme 2 (hACE2) receptor–mimicking hybrid ligand that recruits the hACE2-derived receptor binding domain–interacting peptide to directly interact with a binding hotspot of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Experiencing affinity boosting by ~500% to Omicron, the de novo selected hACE2 mimic exhibited a great binding tolerance to all SARS-CoV-2 variants of concern.

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Section: Discussionmentioning

confidence: 99%

De novo selected hACE2 mimics that integrate hotspot peptides with aptameric scaffolds for binding tolerance of SARS-CoV-2 variants

et al. 2022

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“…[98] However, nucleic-acidbased aptamers have proven their ease in loading the samematerial-based genetic drugs, such as short interference RNAs (siRNA) or antisense oligos, expanding the realm of treatable diseases. [99] Rather than being conjugated with multiple drugs, the aptamer itself can be composed of nucleoside analogue drugs. When all natural nucleosides were replaced with clofarabine, ara-guanosine, gemcitabine, and floxuridine, a series of whole drug-constituted aptamers, termed drugtamers, were generated.…”

Section: Nucleic-acid-based Aptamers and Their Derivativesmentioning

confidence: 99%

“…[ 98 ] However, nucleic‐acid‐based aptamers have proven their ease in loading the same‐material‐based genetic drugs, such as short interference RNAs (siRNA) or antisense oligos, expanding the realm of treatable diseases. [ 99 ]…”

Section: Part I: Target‐specific Non‐covalent Bindingmentioning

confidence: 99%

Molecular Complementarity of Proteomimetic Materials for Target‐Specific Recognition and Recognition‐Mediated Complex Functions

Kim

Jung

et al. 2023

Advanced Materials

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transduction to enable survival and adaption. They are composed of long folded chains made up of a variety of 20 different α-amino acids, which form elaborate molecular structures. These structures can then fit counterpart molecules via molecular complementarity, thus enabling them to perform their specific cellular functions (Figure 1). For instance, membrane receptors specifically recognize extracellular ligand molecules and transfer desired molecular signals into the cell across the ligand-impermeable membrane. [1][2][3] Moreover, different membrane channels exist at the cell surface; in response to external stimuli such as pH, temperature, and action potentials, they undergo conformational changes to modulate the permeability of specific ions and metabolites. [4][5][6] The received extracellular signals are then converted into appropriate cellular responses; this process involves the intracellular increase of certain molecules to control transcription factors and regulate gene expression. [7,8] Even within the cell, there are various proteinligand interactions; for example, some metabolites can bind transcription factors, allosterically regulating subsequent transcription by RNA polymerases. [9,10] To manage cellular metabolism, enzymes catalyze more than 5000 biochemical reactions under highly limited physiological conditions (e.g., mild temperature, neutral pH, and low salt concentrations), attributed to their specific substrate binding abilities and effective collaboration with cofactors or coenzymes. [11] The availability of proteins that interact with many different targets benefits a broad range of biological and biotechnological research. Due to the functional diversity and specificity of the proteins, synthetic biology has successfully refined and rewired various cellular functions to solve numerous issues in a diverse range of fields such as agriculture, [12] manufacturing, [13] pharmaceutics, [14] and therapeutics. [15,16] For example, the use of proteins that enable gene recognition and editing has contributed to the emergence of important metabolic and genetic engineering techniques, allowing for the modulation of microbial cell factories that can efficiently produce high-value products, including biofuels, [17] medicines, [14] and biomolecules for industrial use. [18] Moreover, genetically encoded signal transducers As biomolecules essential for sustaining life, proteins are generated from long chains of 20 different α-amino acids that are folded into unique 3D structures. In particular, many proteins have molecular recognition functions owing to their binding pockets, which have complementary shapes, charges, and polarities for specific targets, making these biopolymers unique and highly valuable for biomedical and biocatalytic applications. Based on the understanding of protein structures and microenvironments, molecular complementarity can be exhibited by synthesizable and modifiable materials. This has prompted researchers to explore the proteomimetic potentials of a diverse range of material...

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“…When these complexes were formulated in PBS compared to water, some formulations had faster aggregation and settling kinetics onto the cells, which resulted in more efficient gene editing . However, there is a limit to this phenomenon as large sizes can affect internalization pathways and settling onto adhered cells is not a factor in the case of in vivo studies. , To increase the cell interaction with polyplexes independent of the settling kinetics, cells can also be transfected while lifted or in suspension (for cell types that are cultured both via a suspension or adherent methods). Adhered cell lines can easily be exposed to transfection formulations after detachment and prior to plating .…”

Section: Introductionmentioning

confidence: 99%

Cationic Micelles Outperform Linear Polymers for Delivery of Antisense Oligonucleotides in Serum: An Exploration of Polymer Architecture, Cationic Moieties, and Cell Addition Order

et al. 2022

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Antisense oligonucleotides (ASOs) are an important emerging therapeutic; however, they struggle to enter cells without a delivery vehicle, such as a cationic polymer. To understand the role of polymer architecture for ASO delivery, five linear polymers and five diblock polymers (capable of self-assembly into micelles) were synthesized with varying cationic groups. After complexation of each polymer/micelle with ASO, it was found that less bulky cationic moieties transfected the ASO more effectively. Interestingly, however the ASO internalization trend was the opposite of the transfection trend for cationic moiety, indicating internalization is not the major factor in determining transfection efficiency for this series. Micelleplexes (micelle–ASO complexes) generally enable higher transfection efficacy as compared to polyplexes (linear polymer–ASO complexes). Additionally, the order of addition of cells and complexes was explored. Linear polyplexes showed better transfection efficiency in adhered cells, whereas micelleplexes delivered the ASO more efficiently when the cells and micelleplexes were added simultaneously. This phenomenon may be due to increased cell-complex interactions as micelleplexes have increased colloidal stability compared to polyplexes. These findings emphasize the importance of polymer composition and architecture in governing the cellular interactions necessary for transfection, thus allowing advancement in the design principles for nonviral nucleic acid delivery formulations.

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Systematic Combination of Oligonucleotides and Synthetic Polymers for Advanced Therapeutic Applications

Cited by 7 publications

References 196 publications

De novo selected hACE2 mimics that integrate hotspot peptides with aptameric scaffolds for binding tolerance of SARS-CoV-2 variants

De novo selected hACE2 mimics that integrate hotspot peptides with aptameric scaffolds for binding tolerance of SARS-CoV-2 variants

Molecular Complementarity of Proteomimetic Materials for Target‐Specific Recognition and Recognition‐Mediated Complex Functions

Cationic Micelles Outperform Linear Polymers for Delivery of Antisense Oligonucleotides in Serum: An Exploration of Polymer Architecture, Cationic Moieties, and Cell Addition Order

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