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Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRasG12C. 非共价识别和反应性对优化共价抑制剂的贡献:KRasG12C 案例研究。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2024-07-11 DOI: 10.1021/acschembio.4c00217
Nikolett Péczka, Ivan Ranđelović, Zoltán Orgován, Noémi Csorba, Attila Egyed, László Petri, Péter Ábrányi-Balogh, Márton Gadanecz, András Perczel, József Tóvári, Gitta Schlosser, Tamás Takács, Levente M Mihalovits, György G Ferenczy, László Buday, György M Keserű
{"title":"Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRas<sup>G12C</sup>.","authors":"Nikolett Péczka, Ivan Ranđelović, Zoltán Orgován, Noémi Csorba, Attila Egyed, László Petri, Péter Ábrányi-Balogh, Márton Gadanecz, András Perczel, József Tóvári, Gitta Schlosser, Tamás Takács, Levente M Mihalovits, György G Ferenczy, László Buday, György M Keserű","doi":"10.1021/acschembio.4c00217","DOIUrl":"https://doi.org/10.1021/acschembio.4c00217","url":null,"abstract":"<p><p>Covalent drugs might bear electrophiles to chemically modify their targets and have the potential to target previously undruggable proteins with high potency. Covalent binding of drug-size molecules includes a noncovalent recognition provided by secondary interactions and a chemical reaction leading to covalent complex formation. Optimization of their covalent mechanism of action should involve both types of interactions. Noncovalent and covalent binding steps can be characterized by an equilibrium dissociation constant (<i>K</i><sub>I</sub>) and a reaction rate constant (<i>k</i><sub>inact</sub>), respectively, and they are affected by both the warhead and the scaffold of the ligand. The relative contribution of these two steps was investigated on a prototypic drug target KRAS<sup>G12C</sup>, an oncogenic mutant of KRAS. We used a synthetically more accessible nonchiral core derived from ARS-1620 that was equipped with four different warheads and a previously described KRAS-specific basic side chain. Combining these structural changes, we have synthesized novel covalent KRAS<sup>G12C</sup> inhibitors and tested their binding and biological effect on KRAS<sup>G12C</sup> by various biophysical and biochemical assays. These data allowed us to dissect the effect of scaffold and warhead on the noncovalent and covalent binding event. Our results revealed that the atropisomeric core of ARS-1620 is not indispensable for KRAS<sup>G12C</sup> inhibition, the basic side chain has little effect on either binding step, and warheads affect the covalent reactivity but not the noncovalent binding. This type of analysis helps identify structural determinants of efficient covalent inhibition and may find use in the design of covalent agents.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Quantitative Measurement of Rate of Targeted Protein Degradation. 定量测量目标蛋白质降解率
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2024-07-09 DOI: 10.1021/acschembio.4c00262
Thomas L Lynch, Violeta L Marin, Ryan A McClure, Colin Phipps, Judith A Ronau, Milad Rouhimoghadam, Ashley M Adams, Soumya Kandi, Malerie L Wolke, Andrea G Shergalis, Gregory K Potts, Omprakash Nacham, Paul Richardson, Stephan J Kakavas, Gekleng Chhor, Gary J Jenkins, Kevin R Woller, Scott E Warder, Anil Vasudevan, Justin M Reitsma
{"title":"Quantitative Measurement of Rate of Targeted Protein Degradation.","authors":"Thomas L Lynch, Violeta L Marin, Ryan A McClure, Colin Phipps, Judith A Ronau, Milad Rouhimoghadam, Ashley M Adams, Soumya Kandi, Malerie L Wolke, Andrea G Shergalis, Gregory K Potts, Omprakash Nacham, Paul Richardson, Stephan J Kakavas, Gekleng Chhor, Gary J Jenkins, Kevin R Woller, Scott E Warder, Anil Vasudevan, Justin M Reitsma","doi":"10.1021/acschembio.4c00262","DOIUrl":"https://doi.org/10.1021/acschembio.4c00262","url":null,"abstract":"<p><p>Targeted protein degradation (TPD) is a therapeutic approach that leverages the cell's natural machinery to degrade targets instead of inhibiting them. This is accomplished by using mono- or bifunctional small molecules designed to induce the proximity of target proteins and E3 ubiquitin ligases, leading to ubiquitination and subsequent proteasome-dependent degradation of the target. One of the most significant attributes of the TPD approach is its proposed catalytic mechanism of action, which permits substoichiometric exposure to achieve the desired pharmacological effects. However, apart from one in vitro study, studies supporting the catalytic mechanism of degraders are largely inferred based on potency. A more comprehensive understanding of the degrader catalytic mechanism of action can help aspects of compound development. To address this knowledge gap, we developed a workflow for the quantitative measurement of the catalytic rate of degraders in cells. Comparing a selective and promiscuous BTK degrader, we demonstrate that both compounds function as efficient catalysts of BTK degradation, with the promiscuous degrader exhibiting faster rates due to its ability to induce more favorable ternary complexes. By leveraging computational modeling, we show that the catalytic rate is highly dynamic as the target is depleted from cells. Further investigation of the promiscuous kinase degrader revealed that the catalytic rate is a better predictor of optimal degrader activity toward a specific target compared to degradation magnitude alone. In summary, we present a versatile method for mapping the catalytic activity of any degrader for TPD in cells.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141557349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Repurposed Drug Interferes with Nucleic Acid to Inhibit the Dual Activities of Coronavirus Nsp13. 一种可干扰核酸以抑制冠状病毒 Nsp13 双重活性的重塑药物。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2024-07-09 DOI: 10.1021/acschembio.4c00244
Nathan Soper, Isabelle Yardumian, Eric Chen, Chao Yang, Samantha Ciervo, Aaron L Oom, Ludovic Desvignes, Mark J Mulligan, Yingkai Zhang, Tania J Lupoli
{"title":"A Repurposed Drug Interferes with Nucleic Acid to Inhibit the Dual Activities of Coronavirus Nsp13.","authors":"Nathan Soper, Isabelle Yardumian, Eric Chen, Chao Yang, Samantha Ciervo, Aaron L Oom, Ludovic Desvignes, Mark J Mulligan, Yingkai Zhang, Tania J Lupoli","doi":"10.1021/acschembio.4c00244","DOIUrl":"https://doi.org/10.1021/acschembio.4c00244","url":null,"abstract":"<p><p>The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlighted a critical need to discover more effective antivirals. While therapeutics for SARS-CoV-2 exist, its nonstructural protein 13 (Nsp13) remains a clinically untapped target. Nsp13 is a helicase responsible for unwinding double-stranded RNA during viral replication and is essential for propagation. Like other helicases, Nsp13 has two active sites: a nucleotide binding site that hydrolyzes nucleoside triphosphates (NTPs) and a nucleic acid binding channel that unwinds double-stranded RNA or DNA. Targeting viral helicases with small molecules, as well as the identification of ligand binding pockets, have been ongoing challenges, partly due to the flexible nature of these proteins. Here, we use a virtual screen to identify ligands of Nsp13 from a collection of clinically used drugs. We find that a known ion channel inhibitor, IOWH-032, inhibits the dual ATPase and helicase activities of SARS-CoV-2 Nsp13 at low micromolar concentrations. Kinetic and binding assays, along with computational and mutational analyses, indicate that IOWH-032 interacts with the RNA binding interface, leading to displacement of nucleic acid substrate, but not bound ATP. Evaluation of IOWH-032 with microbial helicases from other superfamilies reveals that it is selective for coronavirus Nsp13. Furthermore, it remains active against mutants representative of observed SARS-CoV-2 variants. Overall, this work provides a new inhibitor for Nsp13 and provides a rationale for a recent observation that IOWH-032 lowers SARS-CoV-2 viral loads in human cells, setting the stage for the discovery of other potent viral helicase modulators.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Glutathione-Based Photoaffinity Probe Identifies Caffeine as a Positive Allosteric Modulator of the Calcium-Sensing Receptor. 基于谷胱甘肽的光亲和探针确定咖啡因是钙传感受体的正性异构调节剂
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2024-07-08 DOI: 10.1021/acschembio.4c00335
Nadee N J Matarage Don, Rayavarapu Padmavathi, Talan D Khasro, Md Rumman U Zaman, Hai-Feng Ji, Jeffrey L Ram, Young-Hoon Ahn
{"title":"Glutathione-Based Photoaffinity Probe Identifies Caffeine as a Positive Allosteric Modulator of the Calcium-Sensing Receptor.","authors":"Nadee N J Matarage Don, Rayavarapu Padmavathi, Talan D Khasro, Md Rumman U Zaman, Hai-Feng Ji, Jeffrey L Ram, Young-Hoon Ahn","doi":"10.1021/acschembio.4c00335","DOIUrl":"https://doi.org/10.1021/acschembio.4c00335","url":null,"abstract":"<p><p>The calcium-sensing receptor (CaSR), abundantly expressed in the parathyroid gland and kidney, plays a central role in calcium homeostasis. In addition, CaSR exerts multimodal roles, including inflammation, muscle contraction, and bone remodeling, in other organs and tissues. The diverse functions of CaSR are mediated by many endogenous and exogenous ligands, including calcium, amino acids, glutathione, cinacalcet, and etelcalcetide, that have distinct binding sites in CaSR. However, strategies to evaluate ligand interactions with CaSR remain limited. Here, we developed a glutathione-based photoaffinity probe, DAZ-G, that analyzes ligand binding to CaSR. We showed that DAZ-G binds to the amino acid binding site in CaSR and acts as a positive allosteric modulator of CaSR. Oxidized and reduced glutathione and phenylalanine effectively compete with DAZ-G conjugation to CaSR, while calcium, cinacalcet, and etelcalcetide have cooperative effects. An unexpected finding was that caffeine effectively competes with DAZ-G's conjugation to CaSR and acts as a positive allosteric modulator of CaSR. The effective concentration of caffeine for CaSR activation (<10 μM) is easily attainable in plasma by ordinary caffeine consumption. Our report demonstrates the utility of a new chemical probe for CaSR and discovers a new protein target of caffeine, suggesting that caffeine consumption can modulate the diverse functions of CaSR.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141553539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Confounding Factors in Targeted Degradation of Short-Lived Proteins. 短寿命蛋白质定向降解过程中的干扰因素
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2024-07-03 DOI: 10.1021/acschembio.4c00152
Vesna Vetma, Laura Casares Perez, Ján Eliaš, Andrea Stingu, Anju Kombara, Teresa Gmaschitz, Nina Braun, Tuncay Ciftci, Georg Dahmann, Emelyne Diers, Thomas Gerstberger, Peter Greb, Giorgia Kidd, Christiane Kofink, Ilaria Puoti, Valentina Spiteri, Nicole Trainor, Harald Weinstabl, Yvonne Westermaier, Claire Whitworth, Alessio Ciulli, William Farnaby, Kirsten McAulay, Aileen B Frost, Nicola Chessum, Manfred Koegl
{"title":"Confounding Factors in Targeted Degradation of Short-Lived Proteins.","authors":"Vesna Vetma, Laura Casares Perez, Ján Eliaš, Andrea Stingu, Anju Kombara, Teresa Gmaschitz, Nina Braun, Tuncay Ciftci, Georg Dahmann, Emelyne Diers, Thomas Gerstberger, Peter Greb, Giorgia Kidd, Christiane Kofink, Ilaria Puoti, Valentina Spiteri, Nicole Trainor, Harald Weinstabl, Yvonne Westermaier, Claire Whitworth, Alessio Ciulli, William Farnaby, Kirsten McAulay, Aileen B Frost, Nicola Chessum, Manfred Koegl","doi":"10.1021/acschembio.4c00152","DOIUrl":"10.1021/acschembio.4c00152","url":null,"abstract":"<p><p>Targeted protein degradation has recently emerged as a novel option in drug discovery. Natural protein half-life is expected to affect the efficacy of degrading agents, but to what extent it influences target protein degradation has not been systematically explored. Using simple mathematical modeling of protein degradation, we find that the natural half-life of a target protein has a dramatic effect on the level of protein degradation induced by a degrader agent which can pose significant hurdles to screening efforts. Moreover, we show that upon screening for degraders of short-lived proteins, agents that stall protein synthesis, such as GSPT1 degraders and generally cytotoxic compounds, deceptively appear as protein-degrading agents. This is exemplified by the disappearance of short-lived proteins such as MCL1 and MDM2 upon GSPT1 degradation and upon treatment with cytotoxic agents such as doxorubicin. These findings have implications for target selection as well as for the type of control experiments required to conclude that a novel agent works as a bona fide targeted protein degrader.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ALTering Cancer by Triggering Telomere Replication Stress through the Stabilization of Promoter G-Quadruplex in SMARCAL1. 通过稳定SMARCAL1的启动子G-四联体触发端粒复制应激,ALTering Cancer。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2024-07-03 DOI: 10.1021/acschembio.4c00285
Suman Panda, Tanaya Roychowdhury, Anindya Dutta, Sourio Chakraborty, Tanya Das, Subhrangsu Chatterjee
{"title":"ALTering Cancer by Triggering Telomere Replication Stress through the Stabilization of Promoter G-Quadruplex in <i>SMARCAL1</i>.","authors":"Suman Panda, Tanaya Roychowdhury, Anindya Dutta, Sourio Chakraborty, Tanya Das, Subhrangsu Chatterjee","doi":"10.1021/acschembio.4c00285","DOIUrl":"https://doi.org/10.1021/acschembio.4c00285","url":null,"abstract":"<p><p>Most of the human cancers are dependent on telomerase to extend the telomeres. But ∼10% of all cancers use a telomerase-independent, homologous recombination mediated pathway called alternative lengthening of telomeres (ALT). Due to the poor prognosis, ALT status is not being considered yet in the diagnosis of cancer. No such specific treatment is available to date for ALT positive cancers. ALT positive cancers are dependent on replication stress to deploy DNA repair pathways to the telomeres to execute homologous recombination mediated telomere extension. SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1) is associated with the ALT telomeres to resolve replication stress thus providing telomere stability. Thus, the dependency on replication stress regulatory factors like SMARCAL1 made it a suitable therapeutic target for the treatment of ALT positive cancers. In this study, we found a significant downregulation of SMARCAL1 expression by stabilizing the G-quadruplex (G4) motif found in the promoter of <i>SMARCAL1</i> by potent G4 stabilizers, like TMPyP4 and BRACO-19. SMARCAL1 downregulation led toward the increased localization of PML (promyelocytic leukemia) bodies in ALT telomeres and triggered the formation of APBs (ALT-associated promyelocytic leukemia bodies) in ALT positive cell lines, increasing telomere replication stress and DNA damage at a genomic level. Induction of replication stress and hyper-recombinogenic phenotype in ALT positive cells mediated by G4 stabilizing molecules already highlighted their possible application as a new therapeutic window to target ALT positive tumors. In accordance with this, our study will also provide a valuable insight toward the development of G4-based ALT therapeutics targeting <i>SMARCAL1.</i></p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
HCV 5-Methylcytosine Enhances Viral RNA Replication through Interaction with m5C Reader YBX1. HCV 5-甲基胞嘧啶通过与 m5C 阅读器 YBX1 相互作用加强病毒 RNA 复制
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2024-07-02 DOI: 10.1021/acschembio.4c00322
Zhu-Li Li, Yan Xie, Yuke Xie, Hongliang Chen, Xiang Zhou, Min Liu, Xiao-Lian Zhang
{"title":"HCV 5-Methylcytosine Enhances Viral RNA Replication through Interaction with m5C Reader YBX1.","authors":"Zhu-Li Li, Yan Xie, Yuke Xie, Hongliang Chen, Xiang Zhou, Min Liu, Xiao-Lian Zhang","doi":"10.1021/acschembio.4c00322","DOIUrl":"https://doi.org/10.1021/acschembio.4c00322","url":null,"abstract":"<p><p>Hepatitis C virus (HCV) is a positive-stranded RNA virus that mainly causes chronic hepatitis, cirrhosis and hepatocellular carcinoma. Recently we confirmed m5C modifications within NS5A gene of HCV RNA genome. However, the roles of the m5C modification and its interaction with host proteins in regulating HCV's life cycle, remain unexplored. Here, we demonstrate that HCV infection enhances the expression of the host m5C reader YBX1 through the transcription factor MAX. YBX1 acts as an m5C reader, recognizing the m5C-modified NS5A C7525 site in the HCV RNA genome and significantly enhancing HCV RNA stability. This m5C-modification is also required for YBX1 colocalization with lipid droplets and HCV Core protein. Moreover, YBX1 facilitates HCV RNA replication, as well as viral assembly/budding. The tryptophan residue at position 65 (W65) of YBX1 is critical for these functions. Knockout of YBX1 or the application of YBX1 inhibitor SU056 suppresses HCV RNA replication and viral protein translation. To our knowledge, this is the first report demonstrating that the interaction between host m5C reader YBX1 and HCV RNA m5C methylation facilitates viral replication. Therefore, hepatic-YBX1 knockdown holds promise as a potential host-directed strategy for HCV therapy.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Engineered Branaplam Aptamers Exploit Structural Elements from Natural Riboswitches. 利用天然核糖开关的结构元素设计 Branaplam Aptamers。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2024-07-02 DOI: 10.1021/acschembio.4c00358
Michael G Mohsen, Matthew K Midy, Aparaajita Balaji, Ronald R Breaker
{"title":"Engineered Branaplam Aptamers Exploit Structural Elements from Natural Riboswitches.","authors":"Michael G Mohsen, Matthew K Midy, Aparaajita Balaji, Ronald R Breaker","doi":"10.1021/acschembio.4c00358","DOIUrl":"https://doi.org/10.1021/acschembio.4c00358","url":null,"abstract":"<p><p>Drug candidates that fail in clinical trials for efficacy reasons might still have favorable safety and bioavailability characteristics that could be exploited. A failed drug candidate could be repurposed if a receptor, such as an aptamer, were created that binds the compound with high specificity. Branaplam is a small molecule that was previously in development to treat spinal muscular atrophy and Huntington's disease. Here, we report the development of a small (48-nucleotide) RNA aptamer for branaplam with a dissociation constant of ∼150 nM. Starting with a combinatorial RNA pool integrating the secondary and tertiary structural scaffold of a Guanine-I riboswitch aptamer interspersed with regions of random sequence, in vitro selection yielded aptamer candidates for branaplam. Reselection and rational design were employed to improve binding of a representative branaplam aptamer candidate. A resulting variant retains the pseudoknot and two of the paired elements (P2 and P3) from the scaffold but lacks the enclosing paired element (P1) that is essential for the function of the natural Guanine-I riboswitch aptamer. A second combinatorial RNA pool based on the scaffold for TPP (thiamin pyrophosphate) riboswitches also yielded a candidate offering additional opportunities for branaplam aptamer development.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tyrosine Sulfation Modulates the Binding Affinity of Chemokine-Targeting Nanobodies. 酪氨酸硫酸化改变了趋化因子靶向纳米抗体的结合亲和力
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2024-06-28 DOI: 10.1021/acschembio.4c00230
Joshua J Dilly, Alexandra L Morgan, Max J Bedding, Jason K K Low, Joel P Mackay, Anne C Conibear, Ram Prasad Bhusal, Martin J Stone, Charlotte Franck, Richard J Payne
{"title":"Tyrosine Sulfation Modulates the Binding Affinity of Chemokine-Targeting Nanobodies.","authors":"Joshua J Dilly, Alexandra L Morgan, Max J Bedding, Jason K K Low, Joel P Mackay, Anne C Conibear, Ram Prasad Bhusal, Martin J Stone, Charlotte Franck, Richard J Payne","doi":"10.1021/acschembio.4c00230","DOIUrl":"https://doi.org/10.1021/acschembio.4c00230","url":null,"abstract":"<p><p>Chemokines are an important family of small proteins integral to leukocyte recruitment during inflammation. Dysregulation of the chemokine-chemokine receptor axis is implicated in many diseases, and both chemokines and their cognate receptors have been the targets of therapeutic development. Analysis of the antigen-binding regions of chemokine-binding nanobodies revealed a sequence motif suggestive of tyrosine sulfation. Given the well-established importance of post-translational tyrosine sulfation of receptors for chemokine affinity, it was hypothesized that the sulfation of these nanobodies may contribute to chemokine binding and selectivity. Four nanobodies (16C1, 9F1, 11B1, and 11F2) were expressed using amber codon suppression to incorporate tyrosine sulfation. The sulfated variant of 16C1 demonstrated significantly improved chemokine binding compared to the non-sulfated counterpart, while the other nanobodies displayed equipotent or reduced affinity upon sulfation. The ability of tyrosine sulfation to modulate chemokine binding, both positively and negatively, could be leveraged for chemokine-targeted sulfo-nanobody therapeutics in the future.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A C-Degron Structure-Based Approach for the Development of Ligands Targeting the E3 Ligase TRIM7. 基于 C-egron 结构的配体靶向 E3 配体 TRIM7 的开发方法。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2024-06-27 DOI: 10.1021/acschembio.4c00301
Christian J Muñoz Sosa, Christopher Lenz, Anton Hamann, Frederic Farges, Johannes Dopfer, Andreas Krämer, Veronika Cherkashyna, Andrey Tarnovskiy, Yurii S Moroz, Ewgenij Proschak, Václav Němec, Susanne Müller, Krishna Saxena, Stefan Knapp
{"title":"A C-Degron Structure-Based Approach for the Development of Ligands Targeting the E3 Ligase TRIM7.","authors":"Christian J Muñoz Sosa, Christopher Lenz, Anton Hamann, Frederic Farges, Johannes Dopfer, Andreas Krämer, Veronika Cherkashyna, Andrey Tarnovskiy, Yurii S Moroz, Ewgenij Proschak, Václav Němec, Susanne Müller, Krishna Saxena, Stefan Knapp","doi":"10.1021/acschembio.4c00301","DOIUrl":"https://doi.org/10.1021/acschembio.4c00301","url":null,"abstract":"<p><p>TRIM7 is a ubiquitin E3 ligase with key regulatory functions, mediating viral infection, tumor biology, innate immunity, and cellular processes, such as autophagy and ferroptosis. It contains a PRYSPRY domain that specifically recognizes degron sequences containing C-terminal glutamine. Ligands that bind to the TRIM7 PRYSPRY domain may have applications in the treatment of viral infections, as modulators of inflammation, and in the design of a new class of PROTACs (PROteolysis TArgeting Chimeras) that mediate the selective degradation of therapeutically relevant proteins (POIs). Here, we developed an assay toolbox for the comprehensive evaluation of TRIM7 ligands. Using TRIM7 degron sequences together with a structure-based design, we developed the first series of peptidomimetic ligands with low micromolar affinity. The terminal carboxylate moiety was required for ligand activity but prevented cell penetration. A prodrug strategy using an ethyl ester resulted in enhanced permeability, which was evaluated using confocal imaging.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141453610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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