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The expanding repertoire of covalent warheads for drug discovery

DRUG DISCOVERY TODAY (2023)

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Sulfamate Acetamides as Self-Immolative Electrophiles for Covalent Ligand-Directed Release Chemistry

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Chemical and biology of sulfur fluoride exchange (SuFEx) click chemistry for drug discovery

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Summary: Compounds containing an S-F bond have attracted great attention in the chemical and biological literature. Sulfonyl fluorides, in particular, are widely used as covalent protein inhibitors and biological probes. The introduction of fluorine atom in drugs has led to improved medicinal properties and revolutionized pharmaceutical development. Sulfonyl fluoride functional group is widely adopted in chemical biology due to its unique balance between reactivity and stability under physiological conditions. Recent developments of sulfonyl fluoride-based compounds have shown potential in various therapeutic applications.

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Discovery, synthesis and mechanism study of 2,3,5-substituted [1,2,4]-thiadiazoles as covalent inhibitors targeting 3C-Like protease of SARS-CoV-2

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Novel dithiocarbamates selectively inhibit 3CL protease of SARS-CoV-2 and other coronaviruses

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Covalent drug discovery using sulfur(VI) fluoride exchange warheads

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Summary: This review highlights the limitations of cysteine labeling in covalent drug discovery and proposes the use of SuFEx chemistry to target a broader range of amino acids. Recent advances in SuFEx medicinal chemistry and chemical biology are described, including the development of covalent chemical probes that selectively engage various amino acid residues. The authors believe that covalent drug candidates utilizing sulfonyl exchange warheads to target residues beyond cysteine have the potential to enter clinical trials in the near future.

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bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements

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Ligand-Directed Chemistry for Protein Labeling for Affinity-Based Protein Analysis

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Cyclopropenone, Cyclopropeniminium Ion, and Cyclopropenethione as Novel Electrophilic Warheads for Potential Target Discovery of Triple-Negative Breast Cancer

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Rhenium(V) Complexes as Cysteine-Targeting Coordinate Covalent Warheads

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Reversible Dual-Covalent Molecular Locking of the 14-3-3/ERR? Protein-Protein Interaction as a Molecular Glue Drug Discovery Approach

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ACR-Based Probe for the Quantitative Profiling of Histidine Reactivity in the Human Proteome

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Multifunctional Photo-Cross-Linking Probes: From Target Protein Searching to Imaging Applications

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ACCOUNTS OF CHEMICAL RESEARCH (2023)

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Profiling Sulfur(VI) Fluorides as Reactive Functionalities for Chemical Biology Tools and Expansion of the Ligandable Proteome

Katharine E. Gilbert et al.

Summary: A comprehensive profiling of sulfur(VI) fluoride reactivity is presented, focusing on fragment binders and optimized probes. The reactivity profile of S-VI-Fs is demonstrated through live cell chemoproteomics. The studies provide insights into the hydrolytic stability, protein reactivity, and chemoproteomic utility of S-VI-Fs, offering a valuable guide for designing ligands containing S-VI-Fs and expanding the liganded proteome.

ACS CHEMICAL BIOLOGY (2023)

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Recent Advances in Covalent Drug Discovery

Daniel Schaefer et al.

Summary: Despite the increasing number of biologics license applications, the development of covalent inhibitors remains a growing field in drug discovery. The successful approval of certain covalent protein kinase inhibitors and the recent discovery of covalent inhibitors for viral proteases represent advancements in covalent drug development. Covalent bonds targeting proteins offer advantages in target selectivity, drug resistance, and administration concentration. The electrophile (warhead) is a crucial factor for covalent inhibitors, dictating selectivity and reactivity, and can be modified through rational designs. Covalent inhibitors are also finding applications in protein degradation and targeting chimeras (PROTACs) for 'undruggable' proteins, as well as in the treatment of SARS-CoV-2.

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Elemental exchange: Bioisosteric replacement of phosphorus by boron in drug design

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Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity

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Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release

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Simultaneous Covalent Modification of K-Ras(G12D) and K-Ras(G12C) with Tunable Oxirane Electrophiles

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Thiomethyltetrazines Are Reversible Covalent Cysteine Warheads Whose Dynamic Behavior can be “Switched Off” via Bioorthogonal Chemistry Inside Live Cells

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Journal of the American Chemical Society (2023)

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Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3s/ERa Protein-Protein Interaction from Nonselective Fragments

Markella Konstantinidou et al.

Summary: The stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. This study presents the structure-based optimization of a nonselective fragment to develop selective and highly potent small-molecule stabilizers. Through determination of the binding modes of 37 compounds and optimization of the stabilizer's structure, potency and selectivity similar to a natural product were achieved.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2023)

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Protein-protein interactions: developing small-molecule inhibitors/stabilizers through covalent strategies

Bobby Lucero et al.

Summary: Covalent modification of target proteins by specific residue labeling is a promising approach for obtaining small-molecule modulators of PPIs with appropriate selectivity and duration of action.

TRENDS IN PHARMACOLOGICAL SCIENCES (2023)

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Pairs of thiol-substituted 1,2,4-triazole-based isomeric covalent inhibitors with tunable reactivity and selectivity

Shiqi Xu et al.

CHINESE CHEMICAL LETTERS (2023)

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Proximity-Based Modalities for Biology and Medicine

Xingui Liu et al.

Summary: Proximity agents are emerging modalities that can change the fate of target proteins and modulate biological processes. They induce proximity between a target and an effector protein, and strengthening or creating neoproximity can expand the target space with high selectivity. This Outlook discusses the diverse mechanisms and molecules based on induced proximity, highlighting opportunities and challenges for biopharmaceutical innovation.

ACS CENTRAL SCIENCE (2023)

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Targeted Degradation of DNA/RNA Binding Proteins via Covalent Hydrophobic Tagging

Yan Wang et al.

Summary: A new strategy called LACHT has been developed to degrade previously undruggable DNA/RNA binding proteins. This strategy utilizes a noncovalent protein ligand to covalently label the protein target with a reactive N-acyl-N-alkyl sulfonamide group, leading to proteolytic degradation through cellular quality control mechanism. This study provides a generalizable TPD platform for biomedical applications.

CCS CHEMISTRY (2023)

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Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3s/ERa Protein-Protein Interaction from Nonselective Fragments

Markella Konstantinidou et al.

Summary: The stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. In this study, selective and potent small-molecule stabilizers for the 14-3-3s/ERa complex were optimized through structure-based optimization. By targeting specific amino acids and locking the conformation, the optimized covalent stabilizer achieved potency, cooperativity, and selectivity similar to a natural product. The study highlights the value of addressing structure, kinetics, and cooperativity in molecular glue development.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2023)

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Identification of an autoinhibitory, mitophagy-inducing peptide derived from the transmembrane domain of USP30

Xuan Qin et al.

Summary: In this study, a novel peptide Q14 was identified, which can target mitochondrial-anchored deubiquitinating enzyme USP30 and increase mitophagy through a self-inhibition mechanism and an accelerated autophagosome formation mechanism. These findings provide new insights for the design of inhibitors targeting USP30 or other deubiquitinating enzymes.

AUTOPHAGY (2022)

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Review Pharmacology & Pharmacy

Electrophilic warheads in covalent drug discovery: an overview

Nikolett Peczka et al.

Summary: This review provides an overview of electrophilic warheads used for protein labeling in chemical biology and medicinal chemistry. The warheads are discussed based on targeted residues, mechanism, and selectivity, and analyzed using multiple datasets. Despite the availability of numerous electrophilic warheads, only a fraction of them are used in current drug discovery projects. Recent studies have identified new tractable residues, but the discovery of new warheads for these residues is still needed.

EXPERT OPINION ON DRUG DISCOVERY (2022)

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Article Chemistry, Medicinal

Design and Evaluation of a Novel Peptide-Drug Conjugate Covalently Targeting SARS-CoV-2 Papain-like Protease

Na Liu et al.

Summary: In this study, a novel peptide-drug conjugate was designed to inhibit PLpro in COVID-19. The drug showed promising antiviral effects in vitro and provides a potential option for antiviral drug design.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Article Chemistry, Multidisciplinary

Lysine-Targeting Reversible Covalent Inhibitors with Long Residence Time

Rahi M. Reja et al.

Summary: We report a new reversible lysine conjugation method that shows a unique diazaborine product and slower dissociation kinetics compared to the known iminoboronate chemistry. By incorporating the diazaborine-forming warhead RMR1 into a peptide ligand, we have developed potent and long-acting reversible covalent inhibitors of staphylococcal sortase. The efficacy of sortase inhibition is demonstrated through biochemical and cell-based assays. A comparative study between RMR1 and an iminoboronate-forming warhead emphasizes the importance and potential of modulating bond dissociation kinetics in achieving long-acting reversible covalent inhibitors.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2022)

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Article Biochemistry & Molecular Biology

CovPDB: a high-resolution coverage of the covalent protein-ligand interactome

Mingjie Gao et al.

Summary: CovPDB is the first database dedicated solely to high-resolution cocrystal structures of biologically relevant cP-L complexes, containing 733 proteins and 1,501 ligands relating to 2,294 cP-L complexes.

NUCLEIC ACIDS RESEARCH (2022)

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SOX17 and PAX8 constitute an actionable lineage-survival transcriptional complex in ovarian cancer

Lifeng Lin et al.

Summary: This study identifies SOX17 as a new lineage-survival master transcription factor in epithelial ovarian carcinoma, sharing co-expression pattern with PAX8. Genetic disruption of SOX17 or PAX8 inhibits neoplastic cell viability and downregulates lineage-related transcripts. Small-molecule inhibitors of transcriptional CDKs effectively reduce SOX17 and PAX8 expression, and a novel covalent antagonist exhibits potent anti-tumor activity in xenograft models.

ONCOGENE (2022)

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Article Biochemistry & Molecular Biology

Chemo-Selective Cys-Pen Disulfide for Proximity-Induced Cysteine Cross-Linking

Mei-miao Zhan et al.

Summary: Disulfide-rich architectures are valuable for pharmacological applications, and the ligand-induced conjugate strategy can enhance the potency, selectivity, and duration of action of covalent drugs. Using the cysteine-penicillamine disulfide bond as a ligand-induced covalent bonding warhead, new disulfide bonds can be formed between the protein cysteine near the peptide binding site. This approach has shown potential in developing site-specific covalent inhibitors.

ACS CHEMICAL BIOLOGY (2022)

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Article Biochemistry & Molecular Biology

Improved Electrophile Design for Exquisite Covalent Molecule Selectivity

Jose L. Montano et al.

Summary: A method to increase the selectivity of covalent molecules by increasing the steric bulk of the electrophilic warhead is developed. The modified molecules show reduced off-target reactivity and improved selectivity, while retaining the reactivity rates of the original molecule.

ACS CHEMICAL BIOLOGY (2022)

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Article Chemistry, Analytical

Low-Toxicity Sulfonium-Based Probes for Cysteine-Specific Profiling in Live Cells

Rui Wang et al.

Summary: This study reports a set of cysteine-reactive sulfonium-based probes that can label reactive cysteine sites in cellular proteins. These water-soluble probes exhibit enhanced stability, specificity, and compatibility with quantitative proteomic profiling.

ANALYTICAL CHEMISTRY (2022)

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Article Chemistry, Multidisciplinary

Cell-Active, Reversible, and Irreversible Covalent Inhibitors That Selectively Target the Catalytic Lysine of BCR-ABL Kinase

Peng Chen et al.

Summary: This study presents a general approach to develop cell-active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. The strategy was validated by successfully developing covalent inhibitors against BCR-ABL kinase, which showed high selectivity and potency. The salicylaldehyde-containing A5 compound is the first reversible covalent ABL inhibitor with prolonged residence time and minimal off-target effects.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2022)

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Article Chemistry, Multidisciplinary

A bifunctional vinyl-sulfonium tethered peptide induced by thio-Michael-type addition reaction

Hongkun Xu et al.

Summary: The modification and functionalization of peptides play a crucial role in biotechnology and drug development. A highly reactive Michael-type warhead is reported here for the covalent modification of cysteine on peptides and proteins. By incorporating a vinyl group onto a methionine residue, the resulting vinyl sulfonium can be efficiently nucleophilically added by a suitable cysteine residue, leading to the formation of cyclized peptides. This peptide cyclization strategy demonstrates improved cell penetration and stability. Furthermore, a peptide ligand containing vinyl sulfonium can covalently bind to cysteine in the target protein, indicating the potential of vinyl sulfonium as a novel warhead for developing covalent peptide inhibitors.

CHINESE CHEMICAL LETTERS (2022)

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Article Chemistry, Medicinal

3CL Protease Inhibitors with an Electrophilic Arylketone Moiety as Anti-SARS-CoV-2 Agents

Sho Konno et al.

Summary: This study reports the discovery of peptidomimetic compounds that exhibit potent activity against SARS-CoV-2 3CL protease. The most effective inhibitor, YH-53, was found to block virus replication. Structural analysis and additional experimental studies suggest that YH-53 has the potential to be a leading candidate for treating COVID-19.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Article Chemistry, Medicinal

Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability

Bing Bai et al.

Summary: This study describes novel antiviral compounds against coronaviruses, which have good activity and stability, and show effective inhibition of SARS-CoV-2 replication. They also exhibit better selectivity index and broad-spectrum antiviral activity against different types of coronaviruses.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Article Biochemistry & Molecular Biology

Discovery of novel Quinazoline-based KRAS G12C inhibitors as potential anticancer agents

Ling Li et al.

Summary: A series of novel quinazoline analogs were designed and synthesized as KRAS G12C inhibitors, and compound KS-19 showed the highest inhibitory activity against KRAS G12C-mutated cells. Further studies revealed that KS-19 could bind to KRAS G12C protein, decrease its active form, and induce cell apoptosis. In vivo experiments demonstrated that KS-19 effectively suppressed tumor growth in mice carrying KRAS G12C tumors.

BIOORGANIC & MEDICINAL CHEMISTRY (2022)

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Article Oncology

Dual Inhibition of CDK12/CDK13 Targets Both Tumor and Immune Cells in Ovarian Cancer

Lin Cheng et al.

Summary: This study develops a novel CDK12/CDK13 inhibitor that impairs both tumor and immune cells, showing potent anticancer activity in ovarian cancer.

CANCER RESEARCH (2022)

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Article Chemistry, Medicinal

Ynamide Electrophile for the Profiling of Ligandable Carboxyl Residues in Live Cells and the Development of New Covalent Inhibitors

Shengrong Li et al.

Summary: Covalent inhibitors with an electrophilic warhead, such as alpha, beta-unsaturated amide, have shown promising pharmacological properties primarily targeting cysteine or lysine residues. This study explores the potential of ynamide, a versatile building block, to target other amino acids and demonstrates its ability to efficiently modify carboxyl residues. Incorporation of ynamide into kinase inhibitors showed moderate inhibition against EGFR L858R mutant but not against EGFR WT. This novel electrophilic group holds promise for the development of new covalent inhibitors.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Article Chemistry, Medicinal

N-Acylamino Saccharin as an Emerging Cysteine-Directed Covalent Warhead and Its Application in the Identification of Novel FBPase Inhibitors toward Glucose Reduction

Wuqiang Wen et al.

Summary: In this study, N-acylamino saccharin moieties capable of covalent reactions with cysteine were identified and their potential as electrophilic warheads in the treatment of cancer and type 2 diabetes was demonstrated. The cocrystal structure revealed the previously unknown covalent reaction mechanism of saccharin derivatives with cysteine. The title compound displayed potent inhibition of glucose production in vitro and in vivo.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Article Chemistry, Medicinal

Assessment of Reversibility for Covalent Cysteine Protease Inhibitors Using Quantum Mechanics/Molecular Mechanics Free Energy Surfaces

Alberto M. Dos Santos et al.

Summary: We used hybrid quantum mechanics/molecular mechanics (QM/MM) simulations to study the covalent inhibition of cathepsin K and its reversibility. The results suggest that the nucleophilic attack by the catalytic cysteine and proton transfer from the catalytic histidine occur simultaneously. The reaction is more exergonic for alkyne-based inhibitors than for nitrile-based inhibitor odanacatib, which has reversible binding. Additionally, gas-phase energies were calculated to assess electrophilicity of warheads in cysteine protease inhibitor design.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2022)

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Review Biotechnology & Applied Microbiology

Advances in covalent drug discovery

Lydia Boike et al.

Summary: Covalent drugs have been widely used for over a century, but recent advances in tools for rational design have led to the successful development of potent and selective inhibitors, such as KRAS(G12C) inhibitors. The use of electrophile-first approaches and the emergence of chemoproteomics platforms have greatly enhanced the discovery and development of covalent drugs.

NATURE REVIEWS DRUG DISCOVERY (2022)

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Article Chemistry, Organic

A Peptide-Based Ligand-Directed Chemistry Enables Protein Functionalization

Yuena Wang et al.

Summary: The ligand-directed chemistry provides powerful tools for site-specific modification of proteins, and the use of sulfonium warhead enables group transfer. This method can be applied to model proteins and their ligand peptides, and successful cell labeling has been achieved.

ORGANIC LETTERS (2022)

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Article Chemistry, Medicinal

Tunable Cysteine-Targeting Electrophilic Heteroaromatic Warheads Induce Ferroptosis

Endri Karaj et al.

Summary: This article explores the renewed interest in covalent inhibitors in drug discovery and the discovery of a new class of tunable heterocyclic electrophiles capable of inducing ferroptosis. The results show that these heterocycles selectively induce ferroptosis with high potency. Further analysis suggests that these compounds can undergo thiol addition and their potential target is the GPX4 protein. Incorporation of these heterocycles into appropriate pharmacophores generates highly cytotoxic agents.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Review Biochemistry & Molecular Biology

Recent applications of covalent chemistries in protein-protein interaction inhibitors

Alexandria M. Chan et al.

Summary: This study discusses a strategy to develop more effective inhibitors of protein-protein interactions (PPIs) using covalent chemistry. By installing a weakly electrophilic warhead onto a protein ligand scaffold, the reinforcing effect on existing non-covalent interactions and sustained inhibition can be achieved.

RSC MEDICINAL CHEMISTRY (2022)

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Article Biochemistry & Molecular Biology

Selective Covalent Targeting of Anti-apoptotic BFL-1 by a Sulfonium-Tethered Peptide

Na Liu et al.

Summary: Anti-apoptotic BCL-2 family proteins are important targets for cancer treatment, and targeting the BH3-binding pockets can reactivate apoptosis. A novel sulfonium-tethered peptide cyclization strategy was developed to selectively bind to the cysteine(s) of target proteins, leading to the successful construction of a BFL-1 peptide inhibitor, B4-MC, showing promising growth inhibition of BFL-1 over-expressed cancer cell lines.

CHEMBIOCHEM (2021)

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Article Biochemistry & Molecular Biology

CovalentInDB: a comprehensive database facilitating the discovery of covalent inhibitors

Hongyan Du et al.

Summary: Covalent inhibitors, once considered highly adventurous, have seen increased attention in design and discovery due to clinical validation and approval in the past decade. The Covalent Inhibitor Database (CovalentInDB) presented in this study is the largest online resource providing structural information and experimental data for covalent inhibitors. With 4511 inhibitors for 280 protein targets, including 68 approved drugs, the database also offers crystal structures and experimental verification methods for each inhibitor. Users can download high-quality datasets for evaluating and developing computational methods for covalent drug design.

NUCLEIC ACIDS RESEARCH (2021)

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Article Biochemistry & Molecular Biology

Discovery of 4,4′-Dipyridylsulfide Analogs as Switchable Electrophiles for Covalent Inhibition

Yeong-Chan Ahn et al.

Summary: Electrophilic heterocycles are used as covalent fragments for inhibitor and probe development. A focused library of heterocycles for which protonation can enhance reactivity is screened, leading to the identification of new covalent fragments. Mechanistic studies reveal selective covalent S-pyridinylation of the active-site Cys by a neighboring Asp residue through the use of switchable electrophiles.

ACS CHEMICAL BIOLOGY (2021)

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Review Biochemical Research Methods

Bioorthogonal Chemistry and Its Applications

Robert E. Bird et al.

Summary: Bioorthogonal chemistry is a method using non-native functional groups to explore biology in living organisms. This review summarizes common reactions in bioorthogonal methods and the frequency of bioorthogonal applications on different types of biomolecules. The application of bioorthogonal chemistry in imaging, drug delivery, and protein surface attachment is discussed, highlighting its current limitations and potential for future productive use.

BIOCONJUGATE CHEMISTRY (2021)

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Article Biochemistry & Molecular Biology

Characterization of an aromatic trifluoromethyl ketone as a new warhead for covalently reversible kinase inhibitor design

Zhen Zhang et al.

Summary: An aromatic trifluoromethyl ketone moiety was characterized as a new warhead for designing covalently reversible kinase inhibitors targeting non-catalytic cysteine residue. It successfully led to the design and synthesis of potent and selective inhibitors for FGFR4 kinase. Furthermore, this functional group was also applied to the discovery of a new JAK3 inhibitor, indicating its potential in designing other kinase inhibitors.

BIOORGANIC & MEDICINAL CHEMISTRY (2021)

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Article Biochemistry & Molecular Biology

Recent progress in covalent warheads for in vivo targeting of endogenous proteins

Naoya Shindo et al.

Summary: Covalent drugs modify endogenous target proteins to exert potent and durable activity, with current focus on developing targeted covalent inhibitors (TCIs) to maximize efficacy and minimize toxicity risks. The characteristics of warheads affect the target selectivity of TCIs.

BIOORGANIC & MEDICINAL CHEMISTRY (2021)

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Article Chemistry, Medicinal

10 years into the resurgence of covalent drugs

Elena De Vita

Summary: In the first decade of targeted covalent inhibition, scientists have made significant progress in reversing the previous trend that hindered the use of covalent inhibition in drug development, especially in the field of kinase inhibitors. The successful entry of KRAS(G12C) covalent inhibitors into clinical trials in 2019 has sparked great interest in the future potential of this area of drug discovery. Despite the achievements, there are still many unanswered questions and areas for improvement in terms of safety and effectiveness.

FUTURE MEDICINAL CHEMISTRY (2021)

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Article Chemistry, Medicinal

Novel Electrophilic Warhead Targeting a Triple-Negative Breast Cancer Driver in Live Cells Revealed by Inverse Drug Discovery

Youlong Fan et al.

Summary: The inverse drug discovery strategy utilizing cyclopropenone as a potent electrophile has led to the specific and efficient modification of the triple-negative breast cancer driver GSTP1 in live cells, resulting in the discovery of potential inhibitors through further optimization and pathway validation.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Article Chemistry, Multidisciplinary

Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity

Chunlong Ma et al.

Summary: This study introduces a rational design of covalent SARS-CoV-2 M-pro inhibitors with novel cysteine reactive warheads, demonstrating potent enzymatic inhibition, antiviral activity, and improved target specificity compared to existing compounds. The promising lead candidates exhibit high selectivity over host proteases and are valuable chemical probes for target validation and potential drug development against SARS-CoV-2.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2021)

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Article Chemistry, Medicinal

Drimane Derivatives as the First Examples of Covalent BH3 Mimetics that Target MCL-1

Florian Daressy et al.

Summary: Drimane sesquiterpenoid dialdehydes are natural compounds that act as potent inhibitors of MCL-1 and BCL-xL, two overexpressed proteins in various cancers, by covalently inhibiting MCL-1 and inducing apoptosis, showing selectivity for MCL-1/BCL-xL-dependent cell lines.

CHEMMEDCHEM (2021)

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Article Chemistry, Medicinal

Design and Characterization of an Intracellular Covalent Ligand for CC Chemokine Receptor 2

Natalia V. Ortiz Zacarias et al.

Summary: Covalently acting inhibitors are increasingly being used as therapeutics and tools in various applications. Compound 14, the first covalent ligand reported for CCR2, shows promise as a unique tool for ongoing and future studies of CCR2 pharmacology.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Article Chemistry, Multidisciplinary

Strategic Design of Catalytic Lysine-Targeting Reversible Covalent BCR-ABL Inhibitors

David Quach et al.

Summary: In this study, a carbonyl boronic acid warhead was utilized to design BCR-ABL inhibitors, targeting the catalytic lysine with improved potency against ABL kinases. Selectivity of these inhibitors largely depends on molecular recognition of the non-covalent pharmacophore, and insights into the interaction of the warhead with the catalytic lysine were provided through cocrystal structures. The off-target evaluation of compounds was performed using label-free mass spectrometry in different mammalian cells.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2021)

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Article Chemistry, Multidisciplinary

Proximity-induced amino-yne reaction for selective MDM4 conjugation via propargylated sulfonium

Chenshan Lian et al.

Summary: This study presents a novel bioorthogonal reaction that occurs at lysine residues through proximity-induced reactivity, providing a viable approach for lysine-targeted covalent inhibition in proteins.

CHINESE CHEMICAL LETTERS (2021)

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Article Cell Biology

Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads

Levente Kollar et al.

Summary: Constitutive- and immunoproteasomes are vital components of the protein homeostasis system. Selective inhibition of immunoproteasomes shows promise for treating various diseases, and two series of compounds targeting proteasomes have been described in this study. The compounds exhibit significant inhibitory activities against specific subunits of the proteasomes, highlighting their potential for developing selective immunoproteasome inhibitors or compounds targeting multiple subunits.

CELLS (2021)

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Article Chemistry, Multidisciplinary

Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry

Rambabu N. Reddi et al.

Summary: This study introduces a new class of alpha-substituted methacrylamides as potential electrophiles for targeted covalent inhibitors, showing higher thiol reactivity and undergoing a conjugated addition-elimination reaction. These electrophiles demonstrated comparable potency and improved selectivity in various assays, making them a versatile addition to the toolbox of targeted covalent inhibitor design.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2021)

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Article Chemistry, Multidisciplinary

Labeling Preferences of Diazirines with Protein Biomolecules

Alexander West et al.

Summary: The reactivity of alkyl and aryl diazirines with amino acids, proteins, and the cell proteome was systematically evaluated, revealing different labeling patterns. Alkyl diazirines preferentially label acidic amino acids in a pH-dependent manner, while aryl-fluorodiazirine labeling occurs mainly through a carbene intermediate. These findings help rationalize the enrichment of specific proteins by alkyl diazirine probes and the higher labeling yields of positively charged probes in cells and in vitro.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2021)

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Review Pharmacology & Pharmacy

Development and application of novel electrophilic warheads in target identification and drug discovery

Yue Liu et al.

Summary: Therapeutic agents that covalently modify amino acid residues play an important role in treating diseases. Novel electrophiles have been developed to bind to different amino acid residues, facilitating protein interrogation and discovery of new drug targets. Activity-based protein profiling is a useful method for assessing protein function and lead compound discovery.

BIOCHEMICAL PHARMACOLOGY (2021)

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Article Chemistry, Medicinal

Discovery of Novel Small-Molecule Inhibitors of SARS-CoV-2 Main Protease as Potential Leads for COVID-19 Treatment

Anjela Manandhar et al.

Summary: Inhibitors targeting the main protease M-pro of the SARS-CoV-2 virus are under development for potential treatment of COVID-19. Compound SIMR-2418 showed promising inhibitory effects with molecular modeling studies revealing its binding characteristics, paving the way for the discovery of potent lead molecules targeting M-pro.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2021)

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Article Chemistry, Medicinal

An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-κB-Inducing Kinase

Islam Al-Khawaldeh et al.

Summary: This study aimed to design C444-targeting covalent inhibitors and demonstrated that alkynyl heterocycles could serve as potential cysteine traps, providing insight into the limited impact of kinase inhibition on cancer cell growth when targeting NIK signaling in tumor cell lines.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Article Chemistry, Medicinal

Self-Masked Aldehyde Inhibitors: A Novel Strategy for Inhibiting Cysteine Proteases

Linfeng Li et al.

Summary: A novel class of self-masked aldehyde inhibitors has been developed for the major cysteine protease of Chagas disease, showing potent and reversible inhibition while potentially improving pharmacokinetic properties. The study also elucidated the kinetic and chemical mechanism of these inhibitors and applied the strategy to design anti-SARS-CoV-2 drugs.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Article Chemistry, Multidisciplinary

Remarkable and Unexpected Mechanism for (S)-3-Amino-4-(difluoromethylenyl)cyclohex-1-ene-1-carboxylic Acid as a Selective Inactivator of Human Ornithine Aminotransferase

Wei Zhu et al.

Summary: This study identified a new selective hOAT inactivator and explored the formation of the final adduct in its structure and active site; employing protein mass spectrometry approaches and crystallographic methods, it revealed an enzyme complex not previously observed in PLP-dependent enzymes; the turnover mechanism of 14 by hOAT was analyzed, providing insights for the further design of selective inactivators and understanding of potential inactivation mechanisms by aminotransferases.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2021)

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Review Biotechnology & Applied Microbiology

Targeting oxidative stress in disease: promise and limitations of antioxidant therapy

Henry Jay Forman et al.

Summary: Oxidative stress plays a role in various diseases, and understanding the mechanisms behind antioxidants and how to enhance antioxidant defences may lead to greater pharmacological success.

NATURE REVIEWS DRUG DISCOVERY (2021)

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Article Multidisciplinary Sciences

Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease

Haixia Su et al.

Summary: The naturally occurring flavonoid myricetin is identified as a non-peptidomimetic and covalent inhibitor of SARS-CoV-2 3CL protease. Crystal structures reveal the pyrogallol group modifies the catalytic cysteine through covalent binding. This study provides insights into the mechanism of action of pyrogallol-containing natural products and offers a template for designing non-peptidomimetic covalent inhibitors against 3CL proteases.

NATURE COMMUNICATIONS (2021)

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Article Biochemistry & Molecular Biology

Covalent PROTACs: the best of both worlds?

Neil P. Grimster

Summary: Covalent PROTACs combine targeted covalent inhibitors (TCIs) and proteolysis targeting chimeras (PROTACs), showing potential for expanding the druggable proteome. While offering advantages, there are also disadvantages to consider.

RSC MEDICINAL CHEMISTRY (2021)

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Review Biochemistry & Molecular Biology

Recent advances in the development of covalent inhibitors

Hyunsoo Kim et al.

Summary: The use of covalent inhibitors in drug discovery has gained significant attention in the 2000s, with over 50 covalent drugs currently on the market and more in development. This review aims to provide an understanding of covalent inhibitors by exploring their characteristics, mechanisms, and potential applications, as well as introducing the latest covalent warheads for inhibitor development.

RSC MEDICINAL CHEMISTRY (2021)

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Review Biochemistry & Molecular Biology

Put a ring on it: application of small aliphatic rings in medicinal chemistry

Matthias R. Bauer et al.

Summary: This review discusses the increasing use of aliphatic three- and four-membered rings in medicinal chemistry, highlighting both their advantages and potential risks. Understanding the characteristics of small ring structures is crucial for enhancing the efficacy and safety of pharmaceuticals.

RSC MEDICINAL CHEMISTRY (2021)

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Article Biochemistry & Molecular Biology

Global targeting of functional tyrosines using sulfur-triazole exchange chemistry

Heung Sik Hahm et al.

NATURE CHEMICAL BIOLOGY (2020)

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Article Chemistry, Medicinal

Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A

Fabian Barthels et al.

CHEMMEDCHEM (2020)

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Article Chemistry, Medicinal

Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors

Brian A. Lanman et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

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Article Chemistry, Organic

A Sulfonium Triggered Thiol-yne Reaction for Cysteine Modification

Zhanfeng Hou et al.

JOURNAL OF ORGANIC CHEMISTRY (2020)

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Review Pharmacology & Pharmacy

Covalent fragment libraries in drug discovery

Aaron Keeley et al.

DRUG DISCOVERY TODAY (2020)

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Article Chemistry, Medicinal

BIreactive: A Machine-Learning Model to Estimate Covalent Warhead Reactivity

Ferruccio Palazzesi et al.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2020)

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Article Chemistry, Medicinal

Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer

Jay B. Fell et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

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Article Chemistry, Medicinal

Selective Covalent Targeting of Mutated EGFR(T790M) with Chlorofluoroacetamide-Pyrimidines

Mami Sato et al.

ACS MEDICINAL CHEMISTRY LETTERS (2020)

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Article Chemistry, Medicinal

Rationally Designed Covalent BCL6 Inhibitor That Targets a Tyrosine Residue in the Homodimer Interface

Mingxing Teng et al.

ACS MEDICINAL CHEMISTRY LETTERS (2020)

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Article Chemistry, Multidisciplinary

2H-Azirine-Based Reagents for Chemoselective Bioconjugation at Carboxyl Residues Inside Live Cells

Nan Ma et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2020)

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Article Chemistry, Multidisciplinary

2-Sulfonylpyridines as Tunable, Cysteine-Reactive Electrophiles

Claudio Zambaldo et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2020)

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Article Chemistry, Multidisciplinary

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors

Kirsten McAulay et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2020)

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Article Biochemistry & Molecular Biology

Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles

John K. Eaton et al.

NATURE CHEMICAL BIOLOGY (2020)

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Article Chemistry, Medicinal

Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4

Robin A. Fairhurst et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

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Article Chemistry, Multidisciplinary

Bicyclobutane Carboxylic Amide as a Cysteine-Directed Strained Electrophile for Selective Targeting of Proteins

Keisuke Tokunaga et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2020)

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Article Biochemistry & Molecular Biology

Covalent inhibition of NSD1 histone methyltransferase

Huang Huang et al.

NATURE CHEMICAL BIOLOGY (2020)

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Article Chemistry, Multidisciplinary

Using sulfuramidimidoyl fluorides that undergo sulfur(vi) fluoride exchange for inverse drug discovery

Gabriel J. Brighty et al.

NATURE CHEMISTRY (2020)

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Article Chemistry, Medicinal

Affinity and Selectivity Assessment of Covalent Inhibitors by Free Energy Calculations

Levente M. Mihalovits et al.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2020)

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Article Chemistry, Medicinal

Bromo-Cyclobutenaminones as New Covalent UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) Inhibitors

David J. Hamilton et al.

PHARMACEUTICALS (2020)

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Article Biochemistry & Molecular Biology

Design, synthesis, andin vitroevaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors

Thomas S. Corrigan et al.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY (2020)

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Article Chemistry, Multidisciplinary

Intramolecular methionine alkylation constructs sulfonium tethered peptides for protein conjugation

Yang Li et al.

CHEMICAL COMMUNICATIONS (2020)

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Review Biochemistry & Molecular Biology

Covalent inhibitors: a rational approach to drug discovery

Fandi Sutanto et al.

RSC MEDICINAL CHEMISTRY (2020)

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Article Chemistry, Multidisciplinary

Cysteine-Selective Phosphonamidate Electrophiles for Modular Protein Bioconjugations

Marc-Andre Kasper et al.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2019)

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Article Mathematical & Computational Biology

PKAD: a database of experimentally measured pKa values of ionizable groups in proteins

Swagata Pahari et al.

DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION (2019)

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Article Biochemistry & Molecular Biology

New Electrophiles and Strategies for Mechanism-Based and Targeted Covalent Inhibitor Design

Sneha Ray et al.

BIOCHEMISTRY (2019)

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Article Biochemistry & Molecular Biology

Characterising covalent warhead reactivity

James S. Martin et al.

BIOORGANIC & MEDICINAL CHEMISTRY (2019)

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Article Biochemistry & Molecular Biology

Highly tunable thiosulfonates as a novel class of cysteine protease inhibitors with anti-parasitic activity against Schistosoma mansoni

D. J. Ward et al.

BIOORGANIC & MEDICINAL CHEMISTRY (2019)

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Review Pharmacology & Pharmacy

Mechanisms of soft and hard electrophile toxicities

Richard M. LoPachin et al.

TOXICOLOGY (2019)

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Article Chemistry, Medicinal

Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

Chuhui Huang et al.

ACS MEDICINAL CHEMISTRY LETTERS (2019)

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Article Chemistry, Multidisciplinary

A Cyclopropene Electrophile that Targets Glutathione S-Transferase Omega-1 in Cells

Gustav J. Wormer et al.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2019)

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Article Biochemistry & Molecular Biology

A Lysine-Targeted Affinity Label for Serine-β-Lactamase Also Covalently Modifies New Delhi Metallo-β-lactamase-1 (NDM-1)

Pei W. Thomas et al.

BIOCHEMISTRY (2019)

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Article Biochemistry & Molecular Biology

Synthesis and Target Identification of a Novel Electrophilic Warhead, 2-Chloromethylquinoline

Feng Ni et al.

BIOCHEMISTRY (2019)

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Article Chemistry, Multidisciplinary

Histidine-Specific Peptide Modification via Visible-Light-Promoted C-H Alkylation

Xiaoping Chen et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2019)

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Article Chemistry, Multidisciplinary

STEFs: Activated Vinylogous Protein-Reactive Electrophiles

Bente K. Hansen et al.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2019)

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Article Chemistry, Medicinal

Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor

Marcus J. C. Long et al.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2019)

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Article Chemistry, Medicinal

Balancing reactivity and antitumor activity: heteroarylthioacetamide derivatives as potent and time-dependent inhibitors of EGFR

Riccardo Castelli et al.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2019)

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Article Chemistry, Medicinal

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

Matthias Gehringer et al.

JOURNAL OF MEDICINAL CHEMISTRY (2019)

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Article Biochemistry & Molecular Biology

Selective and reversible modification of kinase cysteines with chlorofluoroacetamides

Naoya Shindo et al.

NATURE CHEMICAL BIOLOGY (2019)

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Article Chemistry, Multidisciplinary

Diacylfuroxans Are Masked Nitrile Oxides That Inhibit GPX4 Covalently

John K. Eaton et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2019)

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Article Chemistry, Multidisciplinary

Vinylphosphonites for Staudinger-induced chemoselective peptide cyclization and functionalization

Marc-Andre Kasper et al.

CHEMICAL SCIENCE (2019)

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Article Chemistry, Multidisciplinary

A sulfonium tethered peptide ligand rapidly and selectively modifies protein cysteine in vicinity

Dongyuan Wang et al.

CHEMICAL SCIENCE (2019)

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Article Biochemistry & Molecular Biology

The Nitro Group as a Masked Electrophile in Covalent Enzyme Inhibition

Sneha Ray et al.

ACS CHEMICAL BIOLOGY (2018)

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Article Biochemistry & Molecular Biology

The Taxonomy of Covalent Inhibitors

Alfred Tuley et al.

BIOCHEMISTRY (2018)

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Review Chemistry, Multidisciplinary

Cysteine-reactive probes and their use in chemical proteomics

Dominic G. Hoch et al.

CHEMICAL COMMUNICATIONS (2018)

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Review Chemistry, Multidisciplinary

Structure-based design of targeted covalent inhibitors

Richard Lonsdale et al.

CHEMICAL SOCIETY REVIEWS (2018)

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Review Biochemistry & Molecular Biology

Beyond cysteine: recent developments in the area of targeted covalent inhibition

Herschel Mukherjee et al.

CURRENT OPINION IN CHEMICAL BIOLOGY (2018)

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Article Chemistry, Medicinal

Phenylthiomethyl Ketone-Based Fragments Show Selective and Irreversible Inhibition of Enteroviral 3C Proteases

Robert Schulz et al.

JOURNAL OF MEDICINAL CHEMISTRY (2018)

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Article Chemistry, Medicinal

Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315

Clarissa G. Jakob et al.

JOURNAL OF MEDICINAL CHEMISTRY (2018)

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Article Chemistry, Multidisciplinary

L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib

D. Callegari et al.

CHEMICAL SCIENCE (2018)

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Article Chemistry, Physical

Combined Biophysical Chemistry Reveals a New Covalent Inhibitor with a Low-Reactivity Alkyl Halide

Tang Li et al.

JOURNAL OF PHYSICAL CHEMISTRY LETTERS (2018)

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Article Multidisciplinary Sciences

Optimized arylomycins are a new class of Gram-negative antibiotics

Peter A. Smith et al.

NATURE (2018)

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Article Multidisciplinary Sciences

Targeting STING with covalent small-molecule inhibitors

Simone M. Haag et al.

NATURE (2018)

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Review Biochemistry & Molecular Biology

The Rhomboid Superfamily: Structural Mechanisms and Chemical Biology Opportunities

Anezka Ticha et al.

TRENDS IN BIOCHEMICAL SCIENCES (2018)

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Article Multidisciplinary Sciences

Novel insight into the reaction of nitro, nitroso and hydroxylamino benzothiazinones and of benzoxacinones with Mycobacterium tuberculosis DprE1

Adrian Richter et al.

SCIENTIFIC REPORTS (2018)

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Article Chemistry, Medicinal

A road map for prioritizing warheads for cysteine targeting covalent inhibitors

Peter Abranyi-Balogh et al.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2018)

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Article Chemistry, Medicinal

Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors

Agustin Casimiro-Garcia et al.

JOURNAL OF MEDICINAL CHEMISTRY (2018)

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Article Biochemical Research Methods

A Perspective on the Kinetics of Covalent and Irreversible Inhibition

John M. Strelow

SLAS DISCOVERY (2017)

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Review Chemistry, Medicinal

Covalent inhibitors design and discovery

Stephane De Cesco et al.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2017)

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Article Chemistry, Medicinal

Expanding the Armory: Predicting and Tuning Covalent Warhead Reactivity

Richard Lonsdale et al.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2017)

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Article Chemistry, Medicinal

Determining Cysteines Available for Covalent Inhibition Across the Human Kinome

Zheng Zhao et al.

JOURNAL OF MEDICINAL CHEMISTRY (2017)

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Article Chemistry, Multidisciplinary

Can Relative Binding Free Energy Predict Selectivity of Reversible Covalent Inhibitors?

Payal Chatterjee et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2017)

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Article Chemistry, Multidisciplinary

Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity

Justin M. Lopchuk et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2017)

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Article Chemistry, Multidisciplinary

Diverse Redoxome Reactivity Profiles of Carbon Nucleophiles

Vinayak Gupta et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2017)

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Review Biochemistry & Molecular Biology

Developments of bioorthogonal handle-containing photo-crosslinkers for photoaffinity labeling

Haijun Guo et al.

MEDCHEMCOMM (2017)

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Article Pharmacology & Pharmacy

Insight into the mode of action and selectivity of PBRM, a covalent steroidal inhibitor of 17β-hydroxysteroid dehydrogenase type 1

Alexandre Trottier et al.

BIOCHEMICAL PHARMACOLOGY (2017)

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Review Biochemistry & Molecular Biology

Covalent inhibitors: an opportunity for rational target selectivity

Roman Lagoutte et al.

CURRENT OPINION IN CHEMICAL BIOLOGY (2017)

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Review Biochemistry & Molecular Biology

Modeling covalent-modifier drugs

Ernest Awoonor-Williams et al.

BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS (2017)

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Article Chemistry, Multidisciplinary

Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy-Resistant L858R/T790M/C797S Mutant

Marcel Guenther et al.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2016)

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Review Chemistry, Multidisciplinary

Targeted Covalent Inhibitors for Drug Design

Thomas A. Baillie

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2016)

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Article Biochemistry & Molecular Biology

Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides

Arwin J. Brouwer et al.

BIOORGANIC & MEDICINAL CHEMISTRY (2016)

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Article Chemistry, Medicinal

Recent progress on third generation covalent EGFR inhibitors

Hengmiao Cheng et al.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2016)

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Article Chemistry, Multidisciplinary

Rational design of reversible and irreversible cysteine sulfenic acid-targeted linear C-nucleophiles

Vinayak Gupta et al.

CHEMICAL COMMUNICATIONS (2016)

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Article Chemistry, Physical

Evaluation of Methods for the Calculation of the pKa of Cysteine Residues in Proteins

Ernest Awoonor-Williams et al.

JOURNAL OF CHEMICAL THEORY AND COMPUTATION (2016)

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Article Multidisciplinary Sciences

Strain-release amination

Ryan Gianatassio et al.

SCIENCE (2016)

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Review Biochemistry & Molecular Biology

Covalent protein modification: the current landscape of residue-specific electrophiles

D. Alexander Shannon et al.

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