ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown
Published: May 6, 2025
Language: Английский
Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 7668 - 7758
Published: May 7, 2024
Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with variety new targeted drugs having been approved recent years. A key feature such molecules is an intrinsically reactive group, typically weak electrophile, which enables irreversible or reversible formation bond specific amino acid target protein. This often called "warhead", critical determinant ligand's activity, selectivity, general biological properties. In 2019, we summarized emerging re-emerging warhead chemistries to cysteine acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 62, 5673−5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, field has rapidly evolved. Here discuss progress on warheads made since our last Perspective their application medicinal chemistry chemical biology.
Language: Английский
Citations
55
Medicinal Chemistry Research, Journal Year: 2023, Volume and Issue: 32(6), P. 1039 - 1062
Published: April 29, 2023
Language: Английский
Citations
46
Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(34), P. 15885 - 15893
Published: Aug. 17, 2022
Binding via reversible covalent bond formation presents a novel and powerful mechanism to enhance the potency of synthetic inhibitors for therapeutically important proteins. Work on this front has yielded anticancer drug bortezomib as well antisickling voxelotor. However, rational design remains difficult even when noncovalent are available scaffold. Herein, we report chemically modified phage libraries, both linear cyclic, that incorporate 2-acetylphenylboronic acid (APBA) warhead bind lysines iminoboronate formation. To demonstrate their utility, these APBA-presenting libraries were screened against sortase A Staphylococcus aureus, spike protein SARS-CoV-2. For targets, peptide ligands readily identified with single-digit micromolar excellent specificity, enabling live-cell inhibition highly sensitive detection, respectively. Furthermore, our structure-activity studies unambiguously benefit APBA binding. Overall, contribution shows first time can be developed display interest. The platform should widely applicable proteins including those involved in protein-protein interactions.
Language: Английский
Citations
51
Acta Pharmaceutica Sinica B, Journal Year: 2022, Volume and Issue: 13(5), P. 1990 - 2016
Published: Oct. 22, 2022
Click chemistry has been proven to be very useful in drug delivery. Due the availability of a large number click reactions with various characteristics, selection appropriate for given application is often not trivial task. This review written pharmaceutical researchers who are interested applications and yet may experts. For this, gives an overview available organized by types. Further, general understanding being fast high yielding sometimes overshadows need analyze reaction kinetics assessing suitability certain applications. we highlight relationship among kinetics, concentration effects, time scales, knowing that lack such analysis could easily lead failures. possible issues as chemical stability reagents also discussed aid experimental designs. Recent examples extensive references provided in-depth technical details. We hope this will help those using delivery select reactions/reagents minimize pitfalls.
Language: Английский
Citations
50
Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(29), P. 16069 - 16080
Published: July 14, 2023
Electrophilic small molecules that can reversibly modify proteins are of growing interest in drug discovery. However, the ability to study reversible covalent probes live cells be limited by their reactivity after cell lysis and proteomic workflows, leading scrambling signal loss. We describe how thiomethyltetrazines function as warheads for cysteine modification, this dynamic labeling behavior "switched off" via bioorthogonal chemistry inside cells. Simultaneously, tetrazine serves a reporter enabling introduction tags fluorescent imaging or affinity purification. Thiomethyltetrazines label isolated proteins, cellular lysates, with second-order rate constants spanning 2 orders magnitude (k2, 1–100 M–1 s–1). Reversible modification switched off upon addition trans-cyclooctene cells, converting thiomethyltetrazine tag into Diels–Alder adduct which is stable workflows. Time-course quenching experiments were used demonstrate temporal control over electrophilic modification. Moreover, it shown "locking in" through enables identification protein targets otherwise lost during sample processing. Three further evaluated identify unique pathways live-cell study. anticipate discovery efforts will enabled trifold warheads, reporters, switches stability.
Language: Английский
Citations
26
MedComm – Oncology, Journal Year: 2023, Volume and Issue: 2(4)
Published: Oct. 31, 2023
Abstract Covalent inhibitors have been a rapidly growing field in drug discovery due to their therapeutic potential and unique advantages cancer therapy. As opposed noncovalent inhibitory drugs, covalent reversibly or irreversibly modify proximal nucleophilic amino acid residues on proteins, aiming selectively recognize bind protein targets addressing some of the challenges faced by drugs. Most successful targeted depend primarily binding‐site cysteine residues, but this has limitations for certain that lack targetable residues. Recently, rational design probes targeting other such as lysine, tyrosine, serine, turned out be another promising strategy Thus, development novel strategies extend scope binding improve properties is required. This review gives summary noncysteine from different aspects, including target identification, structure–activity relationships, strategies, properties, hope providing scientific reference future means expanding research
Language: Английский
Citations
26
Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)
Published: Jan. 9, 2024
Abstract Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for preventing future COVID outbreaks. The main protease (M pro ), a cysteine with essential functions in viral replication, has been validated as an effective drug target. Here, we show that M subject to redox regulation vitro and reversibly switches between enzymatically active dimer functionally dormant monomer through modifications residues. These include disulfide-dithiol switch catalytic C145 C117, generation allosteric cysteine-lysine-cysteine SONOS bridge required structural stability under oxidative stress conditions, such those exerted by innate immune system. We identify homo- heterobifunctional reagents mimic switching inhibit activity. discovered are conserved proteases from other coronaviruses, e.g. MERS-CoV SARS-CoV, indicating their potential common druggable sites.
Language: Английский
Citations
16
Chemical Science, Journal Year: 2024, Volume and Issue: 15(14), P. 5340 - 5348
Published: Jan. 1, 2024
The utilization of the cationic-pyridinium activated ester strategy facilitates chemoselective labeling lysine residues within proteins, enabling activity-based protein profiling (ABPP) both in vitro and live cells.
Language: Английский
Citations
12
Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(13), P. 8516 - 8549
Published: June 24, 2024
Interactions among biomacromolecules, predominantly noncovalent, underpin biological processes. However, recent advancements in biospecific chemistry have enabled the creation of specific covalent bonds between biomolecules, both vitro and vivo. This Review traces evolution proteins, emphasizing role genetically encoded latent bioreactive amino acids. These acids react selectively with adjacent natural groups through proximity-enabled bioreactivity, enabling targeted linkages. We explore various designed to target different protein residues, ribonucleic acids, carbohydrates. then discuss how these novel linkages can drive challenging properties capture transient protein-protein protein-RNA interactions Additionally, we examine application peptides as potential therapeutic agents site-specific conjugates for native antibodies, highlighting their capacity form stable molecules. A significant focus is placed on reactive therapeutics (PERx), a pioneering technology therapeutics. detail its wide-ranging applications immunotherapy, viral neutralization, radionuclide therapy. Finally, present perspective existing challenges within avenues future exploration advancement this rapidly evolving field.
Language: Английский
Citations
11
Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 13, 2025
The elementary mechanism and site studies of nanozyme-based inhibition reactions are ambiguous urgently require advanced nanozymes as mediators to elucidate the effect. To this end, we develop a class featuring single Cu–N catalytic configurations B–O sites binding on porous nitrogen-doped carbon substrate (B6/CuSA) for inducing modulable transfer at atomic level. full redistribution electrons across sites, induced by incorporation, yields B6/CuSA with enhanced peroxidase-like activity versus CuSA. More importantly, CuSA features in cysteine expresses competitive through coordination bonds, an constant 0.048 mM. Benefiting from way nanozymes, possesses mixed approaches noncovalent bonds delivers record-mixed interaction 0.054 mM noncompetitive 0.71 Based CuSA, multichannel sensor array accomplishes detection various cancer cells, normal thiols. design principle work is endowed guidelines preliminary evaluation massive potential thiols, cell discrimination, disease prediction.
Language: Английский
Citations
1