Site-selective modification strategies in antibody–drug conjugates

Chemical Society Reviews, Journal Year: 2020, Volume and Issue: 50(2), P. 1305 - 1353

Published: Dec. 10, 2020

Antibody–drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload cell types. This review summarises advances made in construction homogenous ADCs.

Language: Английский

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Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology

Pharmacological Reviews, Journal Year: 2022, Volume and Issue: 74(3), P. 714 - 770

Published: June 23, 2022

The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, metalloproteinases are proteases capable remodeling extracellular matrix. More recently, MMPs have been demonstrated play numerous additional biologic roles cell signaling, immune regulation, and transcriptional control, all which unrelated degradation In this review, we will present milestones major discoveries MMP research, including various clinical trials for use inhibitors. We discuss reasons behind failures most inhibitors treatment cancer inflammatory diseases. There still misconceptions about pathophysiological best strategies inhibit detrimental functions. This review aims preclinical models human pathologies. new biochemical tools track proteolytic activity vivo ex vivo, addition future pharmacological alternatives functions

Significance Statement

Matrix (MMPs) implicated inflammatory, autoimmune, cancers, pathogen-mediated Initially overlooked, contributions can be both beneficial disease progression resolution. Thousands substrates suggested, few hundred validated. After more than 60 years there remain intriguing enigmas solve regarding biological

Language: Английский

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Boronic acids as building blocks for the construction of therapeutically useful bioconjugates

Chemical Society Reviews, Journal Year: 2019, Volume and Issue: 48(13), P. 3513 - 3536

Published: Jan. 1, 2019

Bioconjugates are multifunctional constructs in which biomolecules like peptides, proteins, vitamins and nucleic acids endowed with the properties of specific payloads. These recently emerged as a new generation high-precision therapeutics, several representatives reaching market. This success stimulated an intense search for biocompatible synthetic methodologies to connect both components control bioconjugate's function. Despite remarkable advances made this field, most technologies developed construction bioconjugates were engineered yield stable that can endure complex physiological conditions. Because this, use reversible covalent bonds synthesis has been rather overlooked, notwithstanding potential strategy generate stimuli responsive may operate areas selective delivery drugs, live-cell imaging theranostic approaches. Boronic well-known class reagents have widely used modern formation C-C C-heteroatom bonds. Apart from boronic exhibit exquisite coordination profile be explored molecular tool featuring mechanisms structure biological bioconjugates. In review, therapeutically useful will discussed, focusing on allow these bioconjugation warheads, central pieces linker structures functional

Language: Английский

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Mass Spectrometry-Based Protein Footprinting for Higher-Order Structure Analysis: Fundamentals and Applications

Chemical Reviews, Journal Year: 2020, Volume and Issue: 120(10), P. 4355 - 4454

Published: April 22, 2020

Proteins adopt different higher-order structures (HOS) to enable their unique biological functions. Understanding the complexities of protein and dynamics requires integrated approaches, where mass spectrometry (MS) is now positioned play a key role. One those approaches footprinting. Although initial demonstration footprinting was for HOS determination protein/nucleic acid binding, concept later adapted MS-based analysis, through which covalent labeling "mark" solvent accessible surface area (SASA) proteins reflect HOS. Hydrogen-deuterium exchange (HDX), deuterium in D2O replaces hydrogen backbone amides, most common example Its advantage that footprint reflects SASA bonding, whereas one drawback reversible. Another slow irreversible functional groups on amino side chains by targeted reagents with high specificity, probing structural changes at selected sites. A third approach reactions fast, species are highly reactive broadly several residue time scale submilliseconds. All these combine constitute problem-solving toolbox enables as valuable tool elucidation. As there has been growing need both academia industry owing its throughput capability, prompt availability, spatial resolution, we present summary history, descriptions, principles, mechanisms, applications approaches. Moreover, highlighted according questions they can answer. This review intended tutorial elucidation reference investigators seeking address science.

Language: Английский

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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 6, 2023

Abstract Undruggable proteins are a class of that often characterized by large, complex structures or functions difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also great opportunity for treatment human diseases and attracted substantial efforts in the field medicine. Therefore, this review, we focus on recent development discovery targeting “undruggable” their application clinic. To make review well organized, discuss strategies proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction targeted nucleic acid-based approach, immunotherapy others.

Language: Английский

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Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation

Cell chemical biology, Journal Year: 2019, Volume and Issue: 26(11), P. 1486 - 1500

Published: Oct. 17, 2019

Language: Английский

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Light-driven post-translational installation of reactive protein side chains

Nature, Journal Year: 2020, Volume and Issue: 585(7826), P. 530 - 537

Published: Sept. 23, 2020

Language: Английский

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NBD-based synthetic probes for sensing small molecules and proteins: design, sensing mechanisms and biological applications

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 50(13), P. 7436 - 7495

Published: Jan. 1, 2021

Compounds with a nitrobenzoxadiazole (NBD) skeleton exhibit high reactivity toward biological nucleophilies accompanied by distinct colorimetric and fluorescent changes, environmental sensitivity, small size, all of which facilitate biomolecular sensing self-assembly.

Language: Английский

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Paramagnetic Chemical Probes for Studying Biological Macromolecules

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(10), P. 9571 - 9642

Published: Jan. 27, 2022

Paramagnetic chemical probes have been used in electron paramagnetic resonance (EPR) and nuclear magnetic (NMR) spectroscopy for more than four decades. Recent years witnessed a great increase the variety of study biological macromolecules (proteins, nucleic acids, oligosaccharides). This Review aims to provide comprehensive overview existing probes, including synthetic approaches, functional properties, selected applications. developments seen, particular, rapid expansion range lanthanoid with anisotropic susceptibilities generation structural restraints based on residual dipolar couplings pseudocontact shifts solution solid state NMR spectroscopy, mostly protein studies. Also many new isotropic suitable measurements relaxation enhancements, as well EPR spectroscopic studies (in particular double techniques) developed employed investigate macromolecules. Notwithstanding large number reported only few found broad application further development dedicated applications is foreseen.

Language: Английский

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The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(12), P. 7782 - 7853

Published: May 15, 2023

The high selectivity and affinity of antibodies toward their antigens have made them a highly valuable tool in disease therapy, diagnosis, basic research. A plethora chemical genetic approaches been devised to make accessible more "undruggable" targets equipped with new functions illustrating or regulating biological processes precisely. In this Review, addition introducing how naked various antibody conjugates (such as antibody-drug conjugates, antibody-oligonucleotide antibody-enzyme etc.) work therapeutic applications, special attention has paid chemistry tools helped optimize the outcome (i.e., enhanced efficacy reduced side effects) facilitate multifunctionalization antibodies, focus on emerging fields such targeted protein degradation, real-time live-cell imaging, catalytic labeling decaging spatiotemporal control well engagement inside cells. With advances modern biotechnology, well-designed derivatives via size miniaturization together efficient delivery systems emerged, which gradually improved our understanding important paved way pursue novel for potential treatments diseases.

Language: Английский

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