Recent advances in chemical protein synthesis: method developments and biological applications

Science China Chemistry, Год журнала: 2024, Номер 67(4), С. 1060 - 1096

Опубликована: Март 12, 2024

Язык: Английский

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The Evolving Landscape of Antibody–Drug Conjugates: In Depth Analysis of Recent Research Progress

Bioconjugate Chemistry, Год журнала: 2023, Номер 34(11), С. 1951 - 2000

Опубликована: Окт. 11, 2023

Antibody–drug conjugates (ADCs) are targeted immunoconjugate constructs that integrate the potency of cytotoxic drugs with selectivity monoclonal antibodies, minimizing damage to healthy cells and reducing systemic toxicity. Their design allows for higher doses drug be administered, potentially increasing efficacy. They currently among most promising classes in oncology, efforts expand their application nononcological indications combination therapies. Here we provide a detailed overview recent advances ADC research consider future directions challenges promoting this platform widespread therapeutic use. We examine data from CAS Content Collection, largest human-curated collection published scientific information, analyze publication landscape reveal exploration trends documents insights into area. also discuss evolution key concepts field, major technologies, development pipelines company focuses, disease targets, stages, investment trends. A comprehensive concept map has been created based on Collection. hope report can serve as useful resource understanding current state knowledge field ADCs remaining fulfill potential.

Язык: Английский

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Selective Protein (Post-)modifications through Dynamic Covalent Chemistry: Self-activated S_NAr Reactions

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Янв. 2, 2025

SNAr reactions were remarkably accelerated using a pretargeting and activating unit based on dynamic covalent chemistry (DCvC). A Cys attack at the C–F bond aromatic ring of salicylaldehyde derivatives was only observed upon iminium formation with neighboring Lys residue model small peptides. Such self-activation ascribed to stronger electron-withdrawing capability respect that parent aldehyde stabilized transition state reaction, together higher preorganization reactive groups in cationic aldiminium species. This approach further applied for functionalization two antibodies. In both cases, presence group close proximity resulted noteworthy increase bioconjugation yields, excellent chemo-selectivity. Whereas modification an IgG1 antibody led stochastic product distributions, microenvironment selectivity noted when employing IgG4, line lower number residues hinge region latter. Additionally, postfunctionalization modified antibodies attained through exchange tethered derivative hydrazides, representing unprecedented "tag modify" selective strategy DCvC.

Язык: Английский

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Emerging Delivery Systems for Enabling Precision Nucleic Acid Therapeutics

ACS Nano, Год журнала: 2025, Номер unknown

Опубликована: Янв. 21, 2025

Nucleic acid therapeutics represent a highly promising treatment approach in modern medicine, treating diseases at the genetic level. However, these face numerous challenges practical applications, particularly regarding their stability, effectiveness, cellular uptake efficiency, and limitations delivering them specifically to target tissues. To overcome obstacles, researchers have developed various innovative delivery systems, including viral vectors, lipid nanoparticles, polymer inorganic protein carriers, exosomes, antibody oligonucleotide conjugates, DNA nanostructure-based systems. These systems enhance therapeutic efficacy of nucleic drugs by improving targeting specificity, half-life vivo. In this review, we systematically discuss different types drugs, analyze major barriers encountered delivery, summarize current research progress emerging We also highlight latest advancements application for diseases, infectious cancer, brain wound healing. This review aims provide comprehensive overview drug systems' status future directions integrating nanotechnology, biomaterials science, gene editing technologies, emphasizing transformative potential precision medicine.

Язык: Английский

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PSMA-targeted radiotheranostics in modern nuclear medicine: then, now, and what of the future?

Theranostics, Год журнала: 2024, Номер 14(8), С. 3043 - 3079

Опубликована: Янв. 1, 2024

In 1853, the perception of prostate cancer (PCa) as a rare ailment prevailed, was described by eminent Londoner surgeon John Adams. Rapidly forward to 2018, landscape dramatically altered. Currently, men face one-in-nine lifetime risk PCa, accentuated improved diagnostic methods and an ageing population. With more than three million in United States alone grappling with this disease, overall succumbing stands at one 39. The intricate clinical biological diversity PCa poses serious challenges terms imaging, ongoing monitoring, disease management. field theranostics, therapeutic approaches that harmoniously merge targeted imaging treatments are integrated. A pivotal player arena is radiotheranostics, employing radionuclides for both therapy, prostate-specific membrane antigen (PSMA) forefront. Clinical milestones have been reached, including FDA- and/or EMA-approved PSMA-targeted radiodiagnostic agents, such [

Язык: Английский

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AJICAP-M: Traceless Affinity Peptide Mediated Conjugation Technology for Site-Selective Antibody–Drug Conjugate Synthesis

Organic Letters, Год журнала: 2024, Номер 26(27), С. 5597 - 5601

Опубликована: Апрель 19, 2024

A traceless site-selective conjugation method, "AJICAP-M", was developed for native antibodies at sites using Fc-affinity peptides, focusing on Lys248 or Lys288. It produces antibody–drug conjugates (ADCs) with consistent drug-to-antibody ratios, enhanced stability, and simplified manufacturing. Comparative in vivo assessment demonstrated AJICAP-M's superior stability over traditional ADCs. This technology has been successfully applied to continuous-flow manufacturing, marking the first achievement ADC production. manuscript outlines methodology its effectiveness

Язык: Английский

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Exo-Cleavable Linkers: Enhanced Stability and Therapeutic Efficacy in Antibody–Drug Conjugates

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(20), С. 18124 - 18138

Опубликована: Окт. 16, 2024

Antibody–drug conjugates (ADCs) combine cytotoxic payloads with monoclonal antibodies through chemical linkers. Finding linkers that both enhance circulatory stability and enable effective tumor payload release remains a challenge. The conventional valine-citrulline (Val-Cit) linker is associated several inherent drawbacks, including hydrophobicity-induced aggregation, limited drug–antibody ratio (DAR), premature release. This study introduces an exolinker approach, repositioning the cleavable peptide at exo position of p-aminobenzylcarbamate moiety, as advancement over linear design, which incorporates hydrophilic glutamic acid, addresses limitations Val-Cit platform improves ADC in vivo profiles. In vitro evaluations showed ADCs reduced release, increased drug-to-antibody ratios, avoided significant even hydrophobic payloads. Furthermore, remained stably attached to presence enzymes like carboxylesterases human neutrophil elastase, indicating potential for favorable safety profile.

Язык: Английский

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Insulin-like Growth Factor 2 (IGF2)-Fused Lysosomal Targeting Chimeras for Degradation of Extracellular and Membrane Proteins

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(44), С. 24272 - 24283

Опубликована: Окт. 30, 2023

Targeted degradation of the cell-surface and extracellular proteins via endogenous lysosomal pathways, such as lysosome-targeting chimeras (LYTACs), has recently emerged an attractive tool to expand scope chemical biology. Herein, we report a series recombinant genetically fused insulin-like growth factor 2 (IGF2), which termed iLYTACs, that can be conveniently obtained in high yield by standard cloning bacterial expression matter days. We showed both type-I IGF2 was suitable affibody or nanobody capable binding specific protein target, type-II iLYTAC (or IGF2-Z), IgG-binding Z domain served universal antibody-binding adaptor, could used for effective targeting various membrane-bound proteins-of-interest. These heterobifunctional iLYTACs are fully encoded produced on large scale from conventional E. coli systems without any form modification. In current study, successfully facilitated cell uptake, localization, efficient disease-relevant targets different mammalian lines, including EGFR, PD-L1, CD20, α-synuclein. The antitumor properties were further validated mouse xenograft model. Overall, represent general modular strategy convenient selective targeted degradation, thus expanding potential applications LYTACs related techniques.

Язык: Английский

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Protein-based delivery systems for RNA delivery

Journal of Controlled Release, Год журнала: 2023, Номер 363, С. 253 - 274

Опубликована: Сен. 28, 2023

Язык: Английский

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Targeted Degradation of Cell‐Surface Proteins via Chaperone‐Mediated Autophagy by Using Peptide‐Conjugated Antibodies

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(18)

Опубликована: Март 13, 2024

Cell-surface proteins are important drug targets but historically have posed big challenges for the complete elimination of their functions. Herein, we report antibody-peptide conjugates (Ab-CMAs) in which a peptide targeting chaperone-mediated autophagy (CMA) was conjugated with commercially available monoclonal antibodies specific cell-surface protein degradation by taking advantage lysosomal pathways. Unique features Ab-CMAs, including receptor- and E3 ligase-independent degradation, feasibility towards different (e.g., epidermal growth factor receptor (EGFR), programmed cell death ligand 1 (PD-L1), human 2 (HER2)) simple change antibody, successful tumor inhibition vivo, make them attractive degraders biomedical research therapeutic applications. As first example employing CMA to degrade from outside in, our findings may also shed new light on CMA, pathway typically cytosolic proteins.

Язык: Английский

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