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

Chemical Reviews, Год журнала: 2023, Номер 123(12), С. 7782 - 7853

Опубликована: Май 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.

Язык: Английский

---

Ultrafast Au(III)-Mediated Arylation of Cysteine

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(18), С. 12365 - 12374

Опубликована: Апрель 24, 2024

Through mechanistic work and rational design, we have developed the fastest organometallic abiotic Cys bioconjugation. As a result, Au(III) bioconjugation reagents enable selective labeling of moieties down to picomolar concentrations allow for rapid construction complex heterostructures from peptides, proteins, oligonucleotides. This showcases how chemistry can be interfaced with biomolecules lead range reactivities that are largely unmatched by classical organic tools.

Язык: Английский

---

Chemical Synthesis of Bioactive Proteins

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(13)

Опубликована: Янв. 20, 2023

Abstract Nature has developed a plethora of protein machinery to operate and maintain nearly every task cellular life. These processes are tightly regulated via post‐expression modifications—transformations that modulate intracellular synthesis, folding, activation. Methods prepare homogeneously precisely modified proteins essential probe their function design new bioactive modalities. Synthetic chemistry contributed remarkably science by allowing the preparation novel biomacromolecules often challenging or impractical common biological means. The ability chemically build modify enabled production molecules with physicochemical properties programmed activity for biomedical research, diagnostic, therapeutic applications. This minireview summarizes recent developments in chemical synthesis produce proteins, emphasis on analogs promising vitro vivo activity.

Язык: Английский

---

Enzymatic Bioconjugation: A Perspective from the Pharmaceutical Industry

JACS Au, Год журнала: 2023, Номер 3(5), С. 1267 - 1283

Опубликована: Май 4, 2023

Enzymes have firmly established themselves as bespoke catalysts for small molecule transformations in the pharmaceutical industry, from early research and development stages to large-scale production. In principle, their exquisite selectivity rate acceleration can also be leveraged modifying macromolecules form bioconjugates. However, available face stiff competition other bioorthogonal chemistries. this Perspective, we seek illuminate applications of enzymatic bioconjugation an expanding palette new drug modalities. With these applications, wish highlight some examples current successes pitfalls using enzymes along pipeline try illustrate opportunities further development.

Язык: Английский

---

Chemical generation of checkpoint inhibitory T cell engagers for the treatment of cancer

Nature Chemistry, Год журнала: 2023, Номер 15(11), С. 1636 - 1647

Опубликована: Июль 24, 2023

Abstract Bispecific T cell engagers (BiTEs), a subset of bispecific antibodies (bsAbs), can promote targeted cancer cell’s death by bringing it close to cytotoxic cell. Checkpoint inhibitory (CiTEs) comprise BiTE core with an added immunomodulatory protein, which serves reverse cancer-cell immune-dampening strategies, improving efficacy. So far, protein engineering has been the main approach generate bsAbs and CiTEs, but improved chemical methods for their generation have recently developed. Homogeneous fragment-based constructed from fragment antigen-binding regions (Fabs) be generated using click chemistry. Here we describe method biotin-functionalized three-protein conjugates, include two CiTE molecules, one containing anti-PD-1 Fab other enzyme, Salmonella typhimurium sialidase. The CiTEs’ efficacy was shown superior that simpler scaffold, sialidase-containing inducing substantially enhanced cell-mediated cytotoxicity in vitro. described here, more generally, enables multi-protein constructs further biological applications.

Язык: Английский

---

Intracellular Protein Delivery: Approaches, Challenges, and Clinical Applications

BME Frontiers, Год журнала: 2023, Номер 5

Опубликована: Дек. 18, 2023

Protein biologics are powerful therapeutic agents with diverse inhibitory and enzymatic functions. However, their clinical use has been limited to extracellular applications due inability cross plasma membranes. Overcoming this physiological barrier would unlock the potential of protein drugs for treatment many intractable diseases. In review, we highlight progress made toward achieving cytosolic delivery recombinant proteins. We start by first considering intracellular as a drug modality compared existing Food Drug Administration-approved modalities. Then, summarize strategies that have reported achieve internalization. These techniques can be broadly classified into 3 categories: physical methods, direct engineering, nanocarrier-mediated delivery. Finally, challenges offer an outlook future advances.

Язык: Английский

---

On-Demand Thio-Succinimide Hydrolysis for the Assembly of Stable Protein–Protein Conjugates

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(30), С. 20709 - 20719

Опубликована: Июль 16, 2024

Chemical post-translational protein–protein conjugation is an important technique with growing applications in biotechnology and pharmaceutical research. Maleimides represent one of the most widely employed bioconjugation reagents. However, challenges associated instability first- second-generation maleimide technologies are yet to be fully addressed. We report development a novel class reagents that can undergo on-demand ring-opening hydrolysis resulting thio-succinimide. This strategy enables rapid assembly conjugates. Thio-succinimide hydrolysis, triggered upon application chemical, photochemical, or enzymatic stimuli, allowed homobifunctional bis-maleimide applied production stable conjugates, complete temporal control. Bivalent bispecific dimers constructed from small binders targeting antigens oncological importance, PD-L1 HER2, were generated high purity, stability, improved functionality compared monomeric building blocks. The modularity approach was demonstrated through elaboration linker moiety bioorthogonal propargyl handle produce protein–protein–fluorophore Furthermore, extending by temporarily masking reactive thiols included higher order trimeric tetrameric single-domain antibody potential for extended proteins greater biochemical complexity immunoglobulin On-demand control thio-succinimide combined facile chemically defined homo- heterodimers constitutes expansion chemical methods available generating

Язык: Английский

---

Microbial Synthesis of High-Molecular-Weight, Highly Repetitive Protein Polymers

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(7), С. 6416 - 6416

Опубликована: Март 29, 2023

High molecular weight (MW), highly repetitive protein polymers are attractive candidates to replace petroleum-derived materials as these protein-based (PBMs) renewable, biodegradable, and have outstanding mechanical properties. However, their high MW sequence features make them difficult synthesize in fast-growing microbial cells sufficient amounts for real applications. To overcome this challenge, various methods were developed PBMs. Here, we review recent strategies the construction of genes, expression proteins from circular mRNAs, synthesis by ligation polymerization. We discuss advantages limitations each method highlight future directions that will lead scalable production PBMs a wide range

Язык: Английский

---

Deciphering the Role of the Ser‐Phosphorylation Pattern on the DNA‐Binding Activity of Max Transcription Factor Using Chemical Protein Synthesis

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(47)

Опубликована: Авг. 29, 2023

The chemical synthesis of site-specifically modified transcription factors (TFs) is a powerful method to investigate how post-translational modifications (PTMs) influence TF-DNA interactions and impact gene expression. Among these TFs, Max plays pivotal role in controlling the expression 15 % genome. activity regulated by PTMs; Ser-phosphorylation at N-terminus considered one key regulatory mechanisms. In this study, we developed practical synthetic strategy prepare homogeneous full-length for first time, explore phosphorylation. We prepared focused library eight variants, with distinct modification patterns, including mono-phosphorylated, doubly phosphorylated analogues Ser2/Ser11 as well fluorescently labeled variants through native ligation. Through comprehensive DNA binding analyses, discovered that phosphorylation position crucial DNA-binding Max. Furthermore, vitro high-throughput analysis using microarrays revealed pattern does not interfere sequence specificity Our work provides insights into Max's on specificity, shedding light PTMs TF function.

Язык: Английский

---

Novel formats of antibody conjugates: recent advances in payload diversity, conjugation, and linker chemistry

Expert Opinion on Biological Therapy, Год журнала: 2023, Номер 23(11), С. 1053 - 1065

Опубликована: Ноя. 2, 2023

Introduction In the field of bioconjugates, focus on antibody – drug conjugates (ADCs) with novel payloads beyond traditional categories potent cytotoxic agents is increasing. These innovative ADCs exhibit various molecular formats, ranging from small-molecule payloads, such as immune agonists and proteolytic agents, to macromolecular oligonucleotides proteins.

Язык: Английский

---