British Journal of Pharmacology最新文献

{"title":"A covalent molecular glue hijacks the E3 ligase MKRN2 to degrade the ribosomal protein RPS7 and induce synthetic lethality in p53-deficient NSCLC cells","authors":"Yuqi Pan,&nbsp;Shengjie Hua,&nbsp;Ruolan Yang,&nbsp;Qinman He,&nbsp;Yan Xu,&nbsp;Zeyu Jiang,&nbsp;Xiaoyang Gong,&nbsp;Shurui Zhang,&nbsp;Xiao Wang,&nbsp;Hongli Yu,&nbsp;Hao Wu,&nbsp;Hongmei Wen,&nbsp;Pin Wang,&nbsp;Bo Hang,&nbsp;Xinzhi Wang","doi":"10.1111/bph.70434","DOIUrl":"10.1111/bph.70434","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Functional inactivation of the tumour suppressor p53 drives therapeutic resistance in non-small cell lung cancer (NSCLC). While targeted protein degradation offers a potential solution, the repertoire of ligandable E3 ligases remains limited. This study aimed to identify and characterise 2,6-didehydroxyspeperomin B (DPB) as a novel covalent molecular glue that targets p53-deficient NSCLC and to elucidate its mechanism of action involving the E3 ligase MKRN2.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Cytotoxicity of DPB was assessed in p53 wild-type and p53-deficient NSCLC cells and orthotopic mouse models. Direct cellular targets were identified using quantitative thiol-reactivity proteomics (QTRP) and validated via biophysical assays and site-directed mutagenesis. The molecular glue mechanism was mapped using co-immunoprecipitation-mass spectrometry and genetic knockout/rescue studies. Downstream effects on ribosome biogenesis and protein synthesis were quantified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>DPB exhibited potent, selective cytotoxicity against p53-deficient NSCLC cells and suppressed tumour growth in vivo, outperforming standard chemotherapy. The E3 ubiquitin ligase MKRN2 was the direct target, with DPB covalently modifying the Cys335 residue. Mechanistically, DPB acted as a molecular glue, creating a neo-interface recruiting the ribosomal protein RPS7 to MKRN2. This induced ubiquitination and proteasomal degradation of RPS7, triggering acute nucleolar stress and apoptosis. The synthetic lethal effect was entirely dependent on a functional MKRN2–RPS7 axis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Our findings identify DPB as a covalent molecular glue that harnesses the previously unexploited E3 ligase MKRN2 to eliminate p53-deficient cancer cells. This work validates the MKRN2–RPS7 axis as a synthetic lethal vulnerability and expands the E3 ligase toolbox for targeted protein degradation, providing a novel therapeutic strategy for drug-resistant NSCLC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> LINKED ARTICLES</h3>\u0000 \u0000 <p>This article is part of a themed issue Re-emergence of Covalent Modulation in Drug Discovery. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.22/issuetoc</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 22","pages":"6663-6684"},"PeriodicalIF":7.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thermodynamic characterisation of covalent ligand binding","authors":"Rebecca Hertzman,&nbsp;Maayan Lavie,&nbsp;Almog Nadir,&nbsp;Ronen Gabizon,&nbsp;Nir London","doi":"10.1111/bph.70574","DOIUrl":"10.1111/bph.70574","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Differential scanning fluorimetry (DSF) is a common and straightforward method to evaluate the thermal stability of proteins and has been heavily used for ligand binding characterisation as well as for screening. One class of compounds that is less typically evaluated by DSF are covalent binders. Here, we assessed the contribution of the covalent bond to protein thermal stabilisation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We evaluated selective covalent binders, as well as non-selective reactive electrophiles, against five model protein targets. To assess DSF in the context of fragment-based electrophile screening, we compared DSF measurements to covalent labelling over a subset of electrophilic fragments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>We show that, in the context of selective binders, the formation of the covalent bond increases thermal stabilisation. However, it is not the covalent bond itself that stabilises the protein, because non-selective irreversible binding was typically neutral or, more often, destabilised the protein. In the context of fragment screening, the magnitude of the thermal shift tended to increase with irreversible labelling, whereas the more reactive fragments tended to destabilise the protein.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Taken together, we suggest DSF as a complementary approach to triage covalent fragment hits, in which fragments that show both labelling and protein stabilisation are predicted to display molecular recognition driven binding and serve as more productive starting points for covalent ligand development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> LINKED ARTICLES</h3>\u0000 \u0000 <p>This article is part of a themed issue Re-emergence of Covalent Modulation in Drug Discovery. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.22/issuetoc</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 22","pages":"6704-6717"},"PeriodicalIF":7.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70574","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interaction with NEGR1 affects mGlu₅ cell signalling and the neuroprotection induced by the positive allosteric modulator VU0409551.","authors":"Jennifer D S Guimaraes, Toniana G Carvalho, Luan A Pereira, Emanuele G Silva, Esther M A Maciel, Gabriella P Torres, Thiago Assis, Pablo L Cardozo, Joao P P de Almeida, Nathalia C Silva, Francesca Pischedda, Giovanni Piccoli, Luciene B Vieira, Juliana Alves-Silva, Fabiola M Ribeiro","doi":"10.1111/bph.70671","DOIUrl":"https://doi.org/10.1111/bph.70671","url":null,"abstract":"<p><strong>Background and purpose: </strong>The metabotropic glutamate receptor mGlu₅ plays an important role in neuronal survival and synaptic plasticity. We and others have shown that mGlu₅ positive allosteric modulators (PAMs) are biased agonists, triggering the activation of neuroprotective pathways and promoting neuronal survival. As mGlu₅ biased pharmacology arises from drug-induced interactions with different protein partners, in this study, we analysed the mGlu₅ interactome to identify novel binding partners capable of modulating receptor cell signalling.</p><p><strong>Experimental approach: </strong>To identify new mGlu₅ partners, we employed mass spectrometry, followed by co-immunoprecipitation experiments, which confirmed the interaction between mGlu₅ and the neuronal growth regulator 1 (NEGR1), a cell adhesion molecule. We next evaluated how NEGR1 affects mGlu₅ cell signalling and cellular distribution using lentivirus transduction on primary neuronal cultures to knockdown NEGR1 expression. We also assessed whether NEGR1 plays a role in the neuroprotective effects of the mGlu5 PAM, VU0409551, by evaluating apoptotic cell death and neurite degeneration.</p><p><strong>Key results: </strong>The interaction between NEGR1 and mGlu₅ is important for mGlu₅ synaptic localization and for its coupling with Homer, thereby modulating cell signalling pathways activated by mGlu₅ receptors. For instance, NEGR1 knockdown led to decreased mGlu₅-dependent activation of ERK1/2 and reduced expression of ARC/ARG3.1 and BDNF. Importantly, NEGR1 knockdown affected mGlu₅ pharmacology, as the neuroprotective effect of VU0409551 was not observed in neurons expressing low levels of NEGR1.</p><p><strong>Conclusions and implications: </strong>These results indicate that NEGR1 is essential for mGlu₅-biased activation of neuroprotective cell signalling pathways and for the neuroprotective effects triggered by VU0409551.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Only time will tell: Modelling the kinetics of covalent inhibitors","authors":"Madeeha I. Ali,&nbsp;Peter J. Tonge","doi":"10.1111/bph.70373","DOIUrl":"10.1111/bph.70373","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <p>The selection and optimization of drug leads is largely driven by equilibrium parameters such as IC₅₀ values. However, this approach does not account for the time-dependence of drug-target interactions, which is important given that drug and target concentrations fluctuate in the human body. A fundamental understanding of drug-target binding kinetics is particularly important when the formation and breakdown of the drug-target complex is slow compared to the rate of drug elimination and becomes critical when dealing with covalent drugs where the drug is irreversibly bound to the target. The parameters that define covalent inhibition, specifically <i>k</i>_inact and <i>K</i>_I, can be determined by quantifying target binding as a function of drug concentration and time. However, such assays are difficult to implement in early stages of drug discovery. Here, we review practical approaches to quantify irreversible inhibition, including progress-curve kinetics, multi-timepoint IC₅₀ fitting (EPIC) for scalable library triage, intact- and peptide-level mass spectrometry to confirm adducts and sites, label-free biophysics (SPR, NMR) for orthogonal validation and washout/jump-dilution experiments to diagnose reversibility and measure residence time (<i>τ</i>). We then describe the translation of these microscopic rates to pharmacology through three system determinants: protein turnover, target vulnerability and pharmacokinetics using case studies from BTK, JAK3, KRAS^G12C and EGFR to illustrate how aligning chemistry with context yields durable efficacy. Finally, we propose reporting standards (IC₅₀ with incubation time; <i>k</i>_inact<i>/K</i>_I; τ; turnover-driven occupancy) and a kinetics-first design paradigm to replace static potency with mechanism-anchored optimization of covalent inhibitors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> LINKED ARTICLES</h3>\u0000 \u0000 <p>This article is part of a themed issue Re-emergence of Covalent Modulation in Drug Discovery. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.22/issuetoc</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 22","pages":"6562-6573"},"PeriodicalIF":7.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146178015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial – Re-emergence of covalent modulation in drug discovery","authors":"Lyn H. Jones","doi":"10.1111/bph.70683","DOIUrl":"10.1111/bph.70683","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> LINKED ARTICLES</h3>\u0000 \u0000 <p>This article is part of a themed issue Re-emergence of Covalent Modulation in Drug Discovery. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.22/issuetoc</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 22","pages":"6559-6561"},"PeriodicalIF":7.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70683","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Covalent drug discovery: Progress against key targets, emerging strategies and lessons learnt","authors":"Charles P. Brown,&nbsp;Alan Armstrong,&nbsp;David J. Mann","doi":"10.1111/bph.70344","DOIUrl":"10.1111/bph.70344","url":null,"abstract":"<p>Covalent drug discovery is currently experiencing a boom in industrial and academic interest. To date, at least 75 covalent drugs have received regulatory approval, targeting both traditional target classes and more challenging proteins for which other approaches failed. In many cases, unique aspects of covalent targeting are essential for the efficacy of the drug molecule. Famous successes include the discovery of therapies targeting KRAS^G12C, EGFR^{L858R, T790M} and BTK, whilst molecules targeting KRAS^G12D, WRN helicase and p53^Y220C have recently been disclosed and will represent significant achievements if they receive regulatory approval. Increased interest in the field has catalysed innovation and advanced theoretical understanding of the distinct considerations resulting from the covalent interaction. Here, we review progress against key covalent drug targets, emphasising notable molecules which exemplify the advantages of a covalent approach.</p><p><b>LINKED ARTICLES:</b> This article is part of a themed issue Re-emergence of Covalent Modulation in Drug Discovery. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.22/issuetoc</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 22","pages":"6574-6606"},"PeriodicalIF":7.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70344","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemoproteomic discovery of a brain-penetrant, covalent NLRP3 inhibitor that binds a novel allosteric pocket","authors":"Donald C. Rogness,&nbsp;Evelyn P. Sievert,&nbsp;Vincent F. Vartabedian,&nbsp;Steffen M. Bernard,&nbsp;Erick Aitchison,&nbsp;William Tao,&nbsp;Mikaela Lindvall,&nbsp;Jing Qian,&nbsp;Christie L. Eissler,&nbsp;Brian E. Nordin,&nbsp;Benjamin D. Horning,&nbsp;Cian Kingston,&nbsp;Kelsey N. Lamb,&nbsp;Joshua C. Bell,&nbsp;Bingwen Lu,&nbsp;Jonathan Pollock,&nbsp;Jun Shi,&nbsp;Roli Khattri,&nbsp;David S. Weinstein,&nbsp;Matthew P. Patricelli,&nbsp;Brian N. Cook,&nbsp;Gabriel M. Simon","doi":"10.1111/bph.70626","DOIUrl":"10.1111/bph.70626","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The NLRP3 inflammasome is an attractive therapeutic target for multiple inflammatory conditions. Although inhibitors have been developed, their chemical diversity is limited, and their properties are not ideal for brain penetrance, which is desirable for treating neuroinflammatory disorders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We applied our chemoproteomics platform to survey our electrophilic fragment collection to identify inhibitors of NLRP3. We focused our attention on compounds that bind Cys463, as this residue was identified as an allosteric sensor of NLRP3 function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>A novel inhibitor series was identified bearing a butynamide electrophile and a unique spirocyclic lactam core. Compounds from this series displayed mid-nanomolar potency and were found to inhibit IL-1β secretion in a Cys463-dependent manner. Cryo-EM structures revealed that ligand binding to Cys463 stabilizes an inactive conformation, thereby preventing structural rearrangements required for inflammasome activation. These compounds displayed attractive pharmacokinetic properties and, notably, Kp,uu values &gt;0.5, suggesting the potential to address neuroinflammatory disorders. Administration of a representative compound to humanized mice resulted in clear NLRP3 Cys463 target-engagement and profound suppression of LPS- and ATP-induced IL-1β secretion, demonstrating clear proof-of-concept in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Chemoproteomics-based ligand discovery is intrinsically function-agnostic and has the potential to identify novel pockets on even well-characterized protein targets. Here, optimization of ligands targeting Cys463 of NLRP3 within a previously uncharacterized allosteric pocket led to a unique and potent inhibitor series with attractive physicochemical and pharmacokinetic properties for the potential treatment of diseases involving aberrant innate immune activation in both central and peripheral tissues.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> LINKED ARTICLES</h3>\u0000 \u0000 <p>This article is part of a themed issue Re-emergence of Covalent Modulation in Drug Discovery. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.22/issuetoc</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 22","pages":"6718-6734"},"PeriodicalIF":7.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70626","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ligandability assessment of interferonopathy-associated proteins using chemoproteomics","authors":"Nathan M. Alba,&nbsp;Carys R. Jones,&nbsp;Ffion L. Jones,&nbsp;Lyn H. Jones","doi":"10.1111/bph.70256","DOIUrl":"10.1111/bph.70256","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <p>Mendelian type I interferonopathies are autoimmune diseases caused by genetic mutations that result in upregulation of interferon signalling. Small molecules that modulate proteins encoded by these genes may drive anti-tumour immunity in cancer patients by increasing interferon levels, but chemical probes and drugs are lacking. Covalent chemoproteomics and structural data were compiled to reveal ligandable cysteines, tyrosines and lysines across diverse proteins associated with interferonopathies. From this analysis, we identified several actionable targets, including ligandable sites on ADAR1, RNASEH2A and SAMHD1, and so our work provides a useful resource for future drug discovery efforts directed towards the development of immunotherapeutics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> LINKED ARTICLES</h3>\u0000 \u0000 <p>This article is part of a themed issue Re-emergence of Covalent Modulation in Drug Discovery. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.22/issuetoc</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 22","pages":"6649-6655"},"PeriodicalIF":7.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Covalent fluorescent probes for 2-arachidonoylglycerol metabolic pathways","authors":"Nick D. F. Puijmbroeck,&nbsp;Mario van der Stelt","doi":"10.1111/bph.70315","DOIUrl":"10.1111/bph.70315","url":null,"abstract":"<p>Covalent fluorescent probes have emerged as versatile chemical tools to visualise active enzymes in complex biological systems. When tailored for specific applications, ranging from activity-based protein profiling for drug development to high spatiotemporal resolution imaging of enzymatic activities, these probes provide unique insights into rapid lipid metabolism. The recent development of reverse-designing optimised inhibitors into probes, together with improved analytical techniques, is rapidly advancing our ability to resolve enzyme function in great detail. In this mini-review, we summarise the current landscape of covalent fluorescent probes for the 2-arachidonoylglycerol (2-AG) metabolising enzymes (diacylglycerol lipase, monoacylglycerol lipase, ABHD6 and ABHD12), highlighting the discoveries they have enabled and discussing strategies to address gaps where probes remain lacking.</p><p><b>LINKED ARTICLES:</b> This article is part of a themed issue Re-emergence of Covalent Modulation in Drug Discovery. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.22/issuetoc</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 22","pages":"6656-6662"},"PeriodicalIF":7.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70315","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting protein–protein interactions with reversible covalent modalities: Non-cysteine chemistries","authors":"Ruchira Basu,&nbsp;Steven Fletcher","doi":"10.1111/bph.70377","DOIUrl":"10.1111/bph.70377","url":null,"abstract":"<p>Protein–protein interactions (PPIs) are central to diverse cellular functions, and represent a rapidly expanding class of therapeutic targets. Advancements in covalent drug design have enabled small-molecule drugs to overcome challenges associated with engaging these targets, such as limited durations of action and difficult-to-drug (expansive, featureless and solvent-exposed) binding sites. Among them, reversible covalent modulators have emerged as a promising approach, by offering a balance of selectivity, sustained engagement, and reduced toxicity. These molecules form transient conjugates with nucleophilic residues at PPI interfaces (and beyond). Cysteine is one such extensively targeted nucleophile in covalent drug discovery and, therefore, a popular amino acid commonly leveraged for reversible covalent drugs. However, because of limitations in its availability and mutational susceptibility, alternative chemistries involving other residues are highly sought. In this review, we discuss emerging reversible electrophile–nucleophile chemistries, with a particular focus on serine and lysine, each of which have the potential to unlock new opportunities for PPI modulations. We also explore specific PPI case studies supporting the repertoire of reversible covalent chemistries beyond cysteine-based strategies.</p><p><b>LINKED ARTICLES:</b> This article is part of a themed issue Re-emergence of Covalent Modulation in Drug Discovery. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.22/issuetoc</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 22","pages":"6607-6626"},"PeriodicalIF":7.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70377","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}