Pnictogen-Centered Cascade Exchangers for Thiol-Mediated Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry DOI Creative Commons

Bumhee Lim,

Takehiro Kato, Céline Besnard

и другие.

JACS Au, Год журнала: 2022, Номер 2(5), С. 1105 - 1114

Опубликована: Март 24, 2022

Dynamic covalent exchange cascades with cellular thiols are of interest to deliver substrates the cytosol and inhibit entry viruses. The best transporters inhibitors known today cyclic cascade exchangers (CAXs), producing a new exchanger every exchange, mostly oligochalcogenides, particularly disulfides. objective this study was expand dynamic chalcogen in thiol-mediated uptake by inserting pnictogen relays. A family pnictogen-expanded disulfides covering As(III), Sb(III), Bi(III) is introduced. Their ability cytosolic delivery explored fluorescently labeled CAXs as transporters. promise inhibiting viral assessed SARS-CoV-2 lentiviral vectors. Oxygen-bridged seven-membered 1,3,2-dithiabismepane rings identified privileged scaffolds. same holds for six-membered 1,3,2-dithiarsinane made from asparagusic acid para-aminophenylarsine oxide, which inactive or toxic when used alone. These chemically complementary As(III) both lentivector at concentrations 10 μM lower. Crystal structures, computational models, kinetics support that inhibition contracted dithiarsinane expanded dithiabismepane coincides occur without release relay benefit noncovalent bonds. leads open perspectives regarding drug well unorthodox approaches toward entry.

Язык: Английский

Biosynthesis and genetic encoding of activated nitriles for fast protein conjugation and tunable fluorogenic labeling DOI
Elwy H. Abdelkader, Haocheng Qianzhu, Gottfried Otting

и другие.

Chem, Год журнала: 2025, Номер unknown, С. 102385 - 102385

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

2
Efficient delivery of a DNA aptamer-based biosensor into plant cells for glucose sensing through thiol-mediated uptake DOI Creative Commons
Quanbing Mou, Xueyi Xue, Yuan Ma

и другие.

Science Advances, Год журнала: 2022, Номер 8(26)

Опубликована: Июнь 29, 2022

DNA aptamers have been widely used as biosensors for detecting a variety of targets. Despite decades success, they not applied to monitor any targets in plants, even though plants are major platform providing oxygen, food, and sustainable products ranging from energy fuels chemicals, high-value such pharmaceuticals. A barrier progress is lack efficient methods deliver into plant cells. We herein report thiol-mediated uptake method that more efficiently delivers Arabidopsis tobacco leaf cells than another state-of-the-art method, nanostructures. Such allowed delivery glucose aptamer sensor sensing glucose. This demonstration opens new avenue apply sensors functional studies various targets, including metabolites, hormones, metal ions, proteins better understanding the biodistribution regulation these species their functions.

Язык: Английский

Процитировано

39
Cyclic 5-membered disulfides are not selective substrates of thioredoxin reductase, but are opened nonspecifically DOI Creative Commons
Jan G. Felber,

Lena Poczka,

Karoline Scholzen

и другие.

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Апрель 1, 2022

The cyclic five-membered disulfide 1,2-dithiolane has been widely used in chemical biology and redox probes. Contradictory reports have described it either as nonspecifically reduced cells, or else a highly specific substrate for thioredoxin reductase (TrxR). Here we show that probes, such "TRFS" are by thiol reductants redox-active proteins, their cellular performance is barely affected TrxR inhibition knockout. Therefore, results of imaging inhibitor screening using 1,2-dithiolanes should not be interpreted reflecting activity, previous studies may need re-evaluation. To understand 1,2-dithiolanes' complex behaviour, probe localisation, environment-dependent fluorescence, reduction-independent ring-opening polymerisation, thiol-dependent uptake must all considered; particular caution needed when co-applying thiophilic inhibitors. We present general approach controlling against assay misinterpretation with reducible to ensure future TrxR-targeted designs robustly evaluated selectivity, better orient research.

Язык: Английский

Процитировано

32
Phosphorothioated DNA Engineered Liposomes as a General Platform for Stimuli‐Responsive Cell‐Specific Intracellular Delivery and Genome Editing DOI
Yan An, Xiaohong Chen, Jie He

и другие.

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(25)

Опубликована: Апрель 27, 2023

Intracellular protein delivery is highly desirable for drug-based cell therapy. Established technologies suffer from poor cell-specific cytosolic delivery, which hampers the targeting therapy of specific populations. A fusogenic liposome system enables but its ability and controllable quite limited. Inspired by kinetics viral fusion, we designed a phosphorothioated DNA coatings-modified to mimic function hemagglutinin. The macromolecular fusion machine docks cargo-loaded liposomes at membrane target cells, triggers upon pH or UV light stimuli, facilitates delivery. Our results showed efficient cell-targeted proteins various sizes charges, indicating plug-in unit on could be general strategy spatial-temporally both in vitro vivo.

Язык: Английский

Процитировано

23
Development of CRISPR/Cas Delivery Systems for In Vivo Precision Genome Editing DOI
Yuxuan Chen, Ping Yuan

Accounts of Chemical Research, Год журнала: 2023, Номер 56(16), С. 2185 - 2196

Опубликована: Авг. 1, 2023

ConspectusClustered, regularly interspaced, short palindromic repeat (CRISPR)/associated protein 9 (CRISPR/Cas9) is emerging as a powerful genome-editing tool, enabling precise and targeted modifications of virtually any genomic sequence in living cells. These technologies have potential therapeutic applications for cancers, metabolic diseases, genetic disorders. However, several major challenges hinder the full realization their potential. Specifically, CRISPR-Cas9 gene editors, whether delivered plasmid DNA, mRNA/sgRNA, or ribonucleoprotein (RNP), exhibit poor membrane permeability, restricting access to intracellular genome, where editing occurs. Additionally, these editors lack tissue organ specificity, raising concerns about off-target at level that causes unwanted genotoxicity. Though range delivery carriers has been developed deliver Cas9 effectiveness often limited by number barriers both extracellular levels. Moreover, prolonged activity increases risk level. Therefore, it crucial develop efficient vectors, along with molecular switches safely regulate activity.In this Account, we summarize our recent achievements developing different types materials can efficiently DNA encoding single-guide RNA (sgRNA), RNP into cells highlight design considerations safe vitro vivo. After elucidating chemical physical factors are responsible encapsulating delivering biomacromolecules, further elucidate how biodegradable polymeric using dynamic disulfide chemistry, emphasize features also introduce integration biomacromolecules microneedle-based transdermal promote genome inflammatory skin Finally, review exploit optical, chemical, control conjunction address spatiotemporal specificity vivo demonstrate precision therapy against cancer colitis treatment proof-of-concept examples. In final part, will progress made propose future directions may impact field based on own research outcomes.

Язык: Английский

Процитировано

20
Supramolecular Genome Editing: Targeted Delivery and Endogenous Activation of CRISPR/Cas9 by Dynamic Host‐Guest Recognition DOI
Bowen Li, Qing Li,

Zidan Qi

и другие.

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(14)

Опубликована: Фев. 7, 2024

Abstract We synthesize supramolecular poly(disulfide) (CPS) containing covalently attached cucurbit[7]uril (CB[7]), which is exploited not only as a carrier to deliver plasmid DNA encoding destabilized Cas9 (dsCas9), but also host include trimethoprim (TMP) by CB[7] moieties through the complexation form TMP@CPS/dsCas9. Once transfected into tumor cells CPS, presence of polyamines can competitively trigger decomplexation TMP@CPS, thereby displacing and releasing TMP from stabilize dsCas9 that target edit genomic locus PLK1 inhibit growth cells. Following systemic administration TMP@CPS/dsCas9 decorated with hyaluronic acid (HA), tumor‐specific editing detected due elevated in microenvironment, greatly minimizing off‐target healthy tissues non‐targeted organs. As metabolism dysregulated wide range disorders, this study offers approach precisely control CRISPR/Cas9 functions under particular pathological contexts.

Язык: Английский

Процитировано

8
Inclusive Pattern Generation Protocols to Decode Thiol-Mediated Uptake DOI Creative Commons

Saidbakhrom Saidjalolov,

Filipe Coelho, Vincent Mercier

и другие.

ACS Central Science, Год журнала: 2024, Номер 10(5), С. 1033 - 1043

Опубликована: Апрель 17, 2024

Thiol-mediated uptake (TMU) is an intriguing enigma in current chemistry and biology. While the appearance of cell-penetrating activity upon attachment cascade exchangers (CAXs) has been observed by many increasingly being used practice, molecular basis TMU essentially unknown. The objective this study was to develop a general protocol decode dynamic covalent networks that presumably account for TMU. Uptake inhibition patterns obtained from removal exchange partners either protein knockdown or alternative inhibitors are aligned with original generated CAX transporters functions (here cell motility). These inclusive reveal four most significant CAXs known today enter cells along three almost orthogonal pathways. Epidithiodiketopiperazines (ETP) preferably integrins disulfide isomerases (PDIs), benzopolysulfanes (BPS) different PDIs, PDIA3, asparagusic acid (AspA), antisense oligonucleotide phosphorothioates (OPS) transferrin receptor can be activated PDIs their respective inhibitors. findings provide solid understand use enable prevent entry into cells.

Язык: Английский

Процитировано

8
Organ/Cell-Selective Intracellular Delivery of Biologics via N-Acetylated Galactosamine-Functionalized Polydisulfide Conjugates DOI
Jianhua Lu,

Yuanhao Dai,

Yahui He

и другие.

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(6), С. 3974 - 3983

Опубликована: Фев. 1, 2024

Biologics, including proteins and antisense oligonucleotides (ASOs), face significant challenges when it comes to achieving intracellular delivery within specific organs or cells through systemic administrations. In this study, we present a novel approach for delivering ASOs liver cells, both in vitro vivo, using conjugates that tether N-acetylated galactosamine (GalNAc)-functionalized, cell-penetrating polydisulfides (PDSs). The method involves the thiol-bearing cargo-mediated ring-opening polymerization of GalNAc-functionalized lipoamide monomers so-called aggregation-induced polymerization, leading formation site-specific protein/ASO-PDS with narrow dispersity. hepatocyte-selective arises from combination factors, first GalNAc binding ASGPR receptors on cell immobilization, subsequent thiol–disulfide exchange occurring surface, promoting internalization. Our findings emphasize critical role close proximity PDS backbone as governs success and, consequently, penetration. These hold tremendous potential overcoming various biological barriers encountered during cell-specific biomacromolecular cargos, opening up new avenues diagnosis treatment range liver-targeting diseases.

Язык: Английский

Процитировано

7
RNA Control via Redox‐Responsive Acylation DOI Creative Commons
Junsong Guo,

Siqin Chen,

Yoshiyuki Onishi

и другие.

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(21)

Опубликована: Март 14, 2024

Abstract Incorporating stimuli‐responsive components into RNA constructs provides precise spatiotemporal control over structures and functions. Despite considerable advancements, the utilization of redox‐responsive stimuli for activation caged RNAs remains scarce. In this context, we present a novel strategy that leverages post‐synthetic acylation coupled with chemistry to exert RNA. To achieve this, design synthesize series acylating reagents specifically tailored introducing disulfide‐containing acyl adducts 2′‐OH groups (“cloaking”). Our data reveal these moieties can be readily appended, effectively blocking catalytic activity folding. We also demonstrate traceless release reactivation (“uncloaking”) through reducing stimuli. By employing strategy, exhibits rapid cellular uptake, effective distribution in cytosol without lysosomal entrapment. anticipate our methodology will accessible laboratories engaged biology holds promise as versatile platform RNA‐based applications.

Язык: Английский

Процитировано

7
Photochemical Stabilization of Self‐Assembled Spherical Nucleic Acids DOI Creative Commons
Sepideh Kaviani,

Haochen Bai,

T. P. Das

и другие.

Small, Год журнала: 2025, Номер unknown

Опубликована: Янв. 10, 2025

Abstract Oligonucleotide therapeutics, including antisense oligonucleotides and small interfering RNA, offer promising avenues for modulating the expression of disease‐associated proteins. However, challenges such as nuclease degradation, poor cellular uptake, unspecific targeting hinder their application. To overcome these obstacles, spherical nucleic acids have emerged versatile tools acid delivery in biomedical applications. Our laboratory has introduced sequence‐defined DNA amphiphiles which self‐assemble aqueous solutions. Despite advantages, self‐assembled SNAs can be inherently fragile due to reliance on non‐covalent interactions fall apart biologically relevant conditions, specifically by interaction with serum Herein, this challenge is addressed introducing two methods covalent crosslinking via UV irradiation. Thymine photodimerization or disulfide at micellar interface enhance SNA stability against human albumin binding. This enhanced stability, particularly crosslinked SNAs, leads increased uptake. Furthermore, results sustained activity accessibility release therapeutic acid, along improvement unaided gene silencing. The findings demonstrate efficient stabilization through crosslinking, influencing release, ultimately, silencing activity. These studies further optimization exploration pre‐clinical, vivo studies.

Язык: Английский

Процитировано

1