Pub Date : 2024-11-21DOI: 10.1016/j.chembiol.2024.06.017
Qian Li , Hanzhong Feng , Qiong Tian , Yun Xiang , Xiaolei Wang , Yong-Xing He , Kui Zhu
The rapid rise of antibiotic resistance calls for the discovery of new antibiotics with distinct antibacterial mechanisms. New target mining is indispensable for developing antibiotics. Plant-microbial antibiotics are appealing to underexplored sources due to a dearth of comprehensive understanding of antibacterial activity and the excavation of new targets. Here, a series of phloroglucinol derivatives of plant-root-associated Pseudomonas fluorescens were synthesized for structure-activity relationship analysis. Notably, 2,4-diproylphloroglucinol (DPPG) displayed efficient bactericidal activity against a wide range of gram-positive bacteria. Importantly, mechanistic study exhibits that DPPG binds to type II NADH dehydrogenase (NDH-2), an essential enzyme catalyzing the transfer of electrons from NADH to quinones in the electron transport chain (ETC), blocking electron transfer in S. aureus. Last, we validated the efficacy of DPPG in vivo through animal infection models. Our findings not only provide a distinct antibiotic lead to treat multidrug resistant pathogens but also identify a promising antibacterial target.
抗生素耐药性的迅速增加要求发现具有独特抗菌机制的新型抗生素。开发抗生素离不开新靶点的挖掘。由于缺乏对抗菌活性的全面了解和新靶点的挖掘，植物微生物抗生素对未充分开发的来源具有吸引力。本文合成了一系列与植物根相关的荧光假单胞菌的氯葡萄糖醇衍生物，并对其进行了结构-活性关系分析。值得注意的是，2,4-二丙基氯葡萄糖醇（DPPG）对多种革兰氏阳性菌具有高效的杀菌活性。重要的是，机理研究表明，DPPG 与 II 型 NADH 脱氢酶（NDH-2）结合，阻断了金黄色葡萄球菌体内的电子传递。最后，我们通过动物感染模型验证了 DPPG 在体内的疗效。我们的研究结果不仅为治疗耐多药病原体提供了一种独特的抗生素线索，还发现了一个很有前景的抗菌靶点。
{"title":"Discovery of antibacterial diketones against gram-positive bacteria","authors":"Qian Li , Hanzhong Feng , Qiong Tian , Yun Xiang , Xiaolei Wang , Yong-Xing He , Kui Zhu","doi":"10.1016/j.chembiol.2024.06.017","DOIUrl":"10.1016/j.chembiol.2024.06.017","url":null,"abstract":"<div><div>The rapid rise of antibiotic resistance calls for the discovery of new antibiotics with distinct antibacterial mechanisms. New target mining is indispensable for developing antibiotics. Plant-microbial antibiotics are appealing to underexplored sources due to a dearth of comprehensive understanding of antibacterial activity and the excavation of new targets. Here, a series of phloroglucinol derivatives of plant-root-associated <em>Pseudomonas fluorescens</em> were synthesized for structure-activity relationship analysis. Notably, 2,4-diproylphloroglucinol (DPPG) displayed efficient bactericidal activity against a wide range of gram-positive bacteria. Importantly, mechanistic study exhibits that DPPG binds to type II NADH dehydrogenase (NDH-2), an essential enzyme catalyzing the transfer of electrons from NADH to quinones in the electron transport chain (ETC), blocking electron transfer in <em>S. aureus</em>. Last, we validated the efficacy of DPPG <em>in vivo</em> through animal infection models. Our findings not only provide a distinct antibiotic lead to treat multidrug resistant pathogens but also identify a promising antibacterial target.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 1874-1884.e6"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1016/j.chembiol.2024.08.003
KeJing Zhang , Juan Wei , SheYu Zhang , Liyan Fei , Lu Guo , Xueying Liu , YiShuai Ji , WenJun Chen , Felipe E. Ciamponi , WeiChang Chen , MengXi Li , Jie Zhai , Ting Fu , Katlin B. Massirer , Yang Yu , Mathieu Lupien , Yong Wei , Cheryl. H. Arrowsmith , Qin Wu , WeiHong Tan
Paclitaxel-resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Here, using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. In addition, type I PRMT inhibition synergies with PRMT5 inhibition in suppressing tumor growth of drug-resistant cells through augmenting perturbation of AURKB-mediated mitotic signaling pathway. These findings are fully recapitulated in a patient-derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.
{"title":"A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer","authors":"KeJing Zhang , Juan Wei , SheYu Zhang , Liyan Fei , Lu Guo , Xueying Liu , YiShuai Ji , WenJun Chen , Felipe E. Ciamponi , WeiChang Chen , MengXi Li , Jie Zhai , Ting Fu , Katlin B. Massirer , Yang Yu , Mathieu Lupien , Yong Wei , Cheryl. H. Arrowsmith , Qin Wu , WeiHong Tan","doi":"10.1016/j.chembiol.2024.08.003","DOIUrl":"10.1016/j.chembiol.2024.08.003","url":null,"abstract":"<div><div>Paclitaxel-resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Here, using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. In addition, type I PRMT inhibition synergies with PRMT5 inhibition in suppressing tumor growth of drug-resistant cells through augmenting perturbation of AURKB-mediated mitotic signaling pathway. These findings are fully recapitulated in a patient-derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 1942-1957.e6"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The lysophosphatidylserine (LysoPS) receptor P2Y10, also known as LPS2, plays crucial roles in the regulation of immune responses and holds promise for the treatment of autoimmune diseases. Here, we report the cryoelectron microscopy (cryo-EM) structure of LysoPS-bound P2Y10 in complex with an engineered G13 heterotrimeric protein. The structure and a mutagenesis study highlight the predominant role of a comprehensive polar network in facilitating the binding and activation of the receptor by LysoPS. This interaction pattern is preserved in GPR174, but not in GPR34. Moreover, our structural study unveils the essential interactions that underlie the Gα13 engagement of P2Y10 and identifies key determinants for Gα12-vs.-Gα13-coupling selectivity, whose mutations selectively disrupt Gα12 engagement while preserving the intact coupling of Gα13. The combined structural and functional studies provide insights into the molecular mechanisms of LysoPS recognition and Gα12/13 coupling specificity.
{"title":"Insights into lysophosphatidylserine recognition and Gα12/13-coupling specificity of P2Y10","authors":"Han Yin , Nozomi Kamakura , Yu Qian , Manae Tatsumi , Tatsuya Ikuta , Jiale Liang , Zhenmei Xu , Ruixue Xia , Anqi Zhang , Changyou Guo , Asuka Inoue , Yuanzheng He","doi":"10.1016/j.chembiol.2024.08.005","DOIUrl":"10.1016/j.chembiol.2024.08.005","url":null,"abstract":"<div><div>The lysophosphatidylserine (LysoPS) receptor P2Y10, also known as LPS<sub>2</sub>, plays crucial roles in the regulation of immune responses and holds promise for the treatment of autoimmune diseases. Here, we report the cryoelectron microscopy (cryo-EM) structure of LysoPS-bound P2Y10 in complex with an engineered G<sub>13</sub> heterotrimeric protein. The structure and a mutagenesis study highlight the predominant role of a comprehensive polar network in facilitating the binding and activation of the receptor by LysoPS. This interaction pattern is preserved in GPR174, but not in GPR34. Moreover, our structural study unveils the essential interactions that underlie the Gα<sub>13</sub> engagement of P2Y10 and identifies key determinants for Gα<sub>12</sub>-vs.-Gα<sub>13</sub>-coupling selectivity, whose mutations selectively disrupt Gα<sub>12</sub> engagement while preserving the intact coupling of Gα<sub>13</sub>. The combined structural and functional studies provide insights into the molecular mechanisms of LysoPS recognition and Gα<sub>12/</sub><sub>13</sub> coupling specificity.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 1899-1908.e5"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1016/j.chembiol.2024.10.012
Arturo Carabias , Guillermo Montoya
Nicotinamide adenine dinucleotide (NAD) is an essential metabolite, and its depletion serves as a common bacterial immune strategy against bacteriophages (phages). In a recent issue of Nature, Osterman et al.1 reveal two phage-encoded NAD restoration pathways, showcasing the phages’ innovative counterstrategies against bacterial immunity and providing insights for developing novel antimicrobial approaches.
烟酰胺腺嘌呤二核苷酸（NAD）是一种重要的代谢物，消耗它是细菌对抗噬菌体（噬菌体）的一种常见免疫策略。在最近一期的《自然》杂志上，Osterman 等人1 揭示了两种噬菌体编码的 NAD 恢复途径，展示了噬菌体对抗细菌免疫的创新策略，并为开发新型抗菌方法提供了启示。
{"title":"NAD reloaded: Hacking bacterial defenses","authors":"Arturo Carabias , Guillermo Montoya","doi":"10.1016/j.chembiol.2024.10.012","DOIUrl":"10.1016/j.chembiol.2024.10.012","url":null,"abstract":"<div><div>Nicotinamide adenine dinucleotide (NAD) is an essential metabolite, and its depletion serves as a common bacterial immune strategy against bacteriophages (phages). In a recent issue of <em>Nature</em>, Osterman et al.<span><span><sup>1</sup></span></span> reveal two phage-encoded NAD restoration pathways, showcasing the phages’ innovative counterstrategies against bacterial immunity and providing insights for developing novel antimicrobial approaches.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 1872-1873"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1016/j.chembiol.2024.06.014
Corinna König , Nikita V. Ivanisenko , Laura K. Hillert-Richter , Deepti Namjoshi , Kalyani Natu , Johannes Espe , Dirk Reinhold , Nikolai A. Kolchanov , Vladimir A. Ivanisenko , Thilo Kähne , Kakoli Bose , Inna N. Lavrik
Activation of procaspase-8 in the death effector domain (DED) filaments of the death-inducing signaling complex (DISC) is a key step in apoptosis. In this study, a rationally designed cell-penetrating peptide, DEDid, was engineered to mimic the h2b helical region of procaspase-8-DED2 containing a highly conservative FL motif. Furthermore, mutations were introduced into the DEDid binding site of the procaspase-8 type I interface. Additionally, our data suggest that DEDid targets other type I DED interactions such as those of FADD. Both approaches of blocking type I DED interactions inhibited CD95L-induced DISC assembly, caspase activation and apoptosis. We showed that inhibition of procaspase-8 type I interactions by mutations not only diminished procaspase-8 recruitment to the DISC but also destabilized the FADD core of DED filaments. Taken together, this study offers insights to develop strategies to target DED proteins, which may be considered in diseases associated with cell death and inflammation.
死亡诱导信号复合体（DISC）的死亡效应域（DED）丝中的procaspase-8被激活是细胞凋亡的关键步骤。在这项研究中，我们设计了一种合理的细胞穿透肽--DEDid，它模仿了procaspase-8-DED2的h2b螺旋区，其中包含一个高度保守的FL基序。此外，我们还在 procaspase-8 I 型界面的 DEDid 结合位点引入了突变。此外，我们的数据还表明，DEDid靶向其他I型DED相互作用，如FADD的相互作用。阻断 I 型 DED 相互作用的两种方法都抑制了 CD95L 诱导的 DISC 组装、caspase 激活和细胞凋亡。我们发现，通过突变抑制procaspase-8的I型相互作用不仅会减少procaspase-8对DISC的招募，还会破坏DED丝的FADD核心的稳定性。综上所述，这项研究为开发靶向 DED 蛋白的策略提供了启示，在与细胞死亡和炎症相关的疾病中可能会考虑到这一点。
{"title":"Targeting type I DED interactions at the DED filament serves as a sensitive switch for cell fate decisions","authors":"Corinna König , Nikita V. Ivanisenko , Laura K. Hillert-Richter , Deepti Namjoshi , Kalyani Natu , Johannes Espe , Dirk Reinhold , Nikolai A. Kolchanov , Vladimir A. Ivanisenko , Thilo Kähne , Kakoli Bose , Inna N. Lavrik","doi":"10.1016/j.chembiol.2024.06.014","DOIUrl":"10.1016/j.chembiol.2024.06.014","url":null,"abstract":"<div><div>Activation of procaspase-8 in the death effector domain (DED) filaments of the death-inducing signaling complex (DISC) is a key step in apoptosis. In this study, a rationally designed cell-penetrating peptide, DEDid, was engineered to mimic the <em>h</em>2b helical region of procaspase-8-DED2 containing a highly conservative FL motif. Furthermore, mutations were introduced into the DEDid binding site of the procaspase-8 type I interface. Additionally, our data suggest that DEDid targets other type I DED interactions such as those of FADD. Both approaches of blocking type I DED interactions inhibited CD95L-induced DISC assembly, caspase activation and apoptosis. We showed that inhibition of procaspase-8 type I interactions by mutations not only diminished procaspase-8 recruitment to the DISC but also destabilized the FADD core of DED filaments. Taken together, this study offers insights to develop strategies to target DED proteins, which may be considered in diseases associated with cell death and inflammation.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 1969-1985.e6"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141754487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1016/j.chembiol.2024.09.010
Guilherme M. Lima , Zeinab Jame-Chenarboo , Mirat Sojitra , Susmita Sarkar , Eric J. Carpenter , Claire Y. Yang , Edward Schmidt , Justine Lai , Alexey Atrazhev , Danial Yazdan , Chuanhao Peng , Elizabeth A. Volker , Ray Ho , Gisele Monteiro , Raymond Lai , Lara K. Mahal , Matthew S. Macauley , Ratmir Derda
Selective detection of disease-associated changes in the glycocalyx is an emerging field in modern targeted therapies. Detecting minor glycan changes on the cell surface is a challenge exacerbated by the lack of correspondence between cellular DNA/RNA and glycan structures. We demonstrate that multivalent displays of lectins on DNA-barcoded phages—liquid lectin array (LiLA)—detect subtle differences in density of glycans on cells. LiLA constructs displaying 73 copies of diCBM40 (CBM) lectin per virion (φ-CBM73) exhibit non-linear ON/OFF-like recognition of sialoglycans on the surface of normal and cancer cells. A high-valency φ-CBM290 display, or soluble CBM protein, cannot amplify the subtle differences detected by φ-CBM73. Similarly, multivalent displays of CBM and Siglec-7 detect differences in the glycocalyx between stem-like and non-stem populations in cancer. Multivalent display of lectins offer in situ detection of minor differences in glycocalyx in cells both in vitro and in vivo not feasible to currently available technologies.
{"title":"The liquid lectin array detects compositional glycocalyx differences using multivalent DNA-encoded lectins on phage","authors":"Guilherme M. Lima , Zeinab Jame-Chenarboo , Mirat Sojitra , Susmita Sarkar , Eric J. Carpenter , Claire Y. Yang , Edward Schmidt , Justine Lai , Alexey Atrazhev , Danial Yazdan , Chuanhao Peng , Elizabeth A. Volker , Ray Ho , Gisele Monteiro , Raymond Lai , Lara K. Mahal , Matthew S. Macauley , Ratmir Derda","doi":"10.1016/j.chembiol.2024.09.010","DOIUrl":"10.1016/j.chembiol.2024.09.010","url":null,"abstract":"<div><div>Selective detection of disease-associated changes in the glycocalyx is an emerging field in modern targeted therapies. Detecting minor glycan changes on the cell surface is a challenge exacerbated by the lack of correspondence between cellular DNA/RNA and glycan structures. We demonstrate that multivalent displays of lectins on DNA-barcoded phages—liquid lectin array (LiLA)—detect subtle differences in density of glycans on cells. LiLA constructs displaying 73 copies of diCBM40 (CBM) lectin per virion (φ-CBM<sub>73</sub>) exhibit non-linear ON/OFF-like recognition of sialoglycans on the surface of normal and cancer cells. A high-valency φ-CBM<sub>290</sub> display, or soluble CBM protein, cannot amplify the subtle differences detected by φ-CBM<sub>73</sub>. Similarly, multivalent displays of CBM and Siglec-7 detect differences in the glycocalyx between stem-like and non-stem populations in cancer. Multivalent display of lectins offer <em>in situ</em> detection of minor differences in glycocalyx in cells both <em>in vitro</em> and <em>in vivo</em> not feasible to currently available technologies.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 1986-2001.e9"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1016/j.chembiol.2024.10.003
Hiroki Miura , Kang-Hsin Wang , Tomoki Inagaki , Frank Chuang , Michiko Shimoda , Chie Izumiya , Tadashi Watanabe , Ryan R. Davis , Clifford G. Tepper , Somayeh Komaki , Ken-ichi Nakajima , Ashish Kumar , Yoshihiro Izumiya
Kaposi’s sarcoma-associated herpesvirus (KSHV) establishes a latent infection, and viral genes are poised to be transcribed in the latent chromatin. In the poised chromatins, KSHV latency-associated nuclear antigen (LANA) interacts with cellular chromodomain-helicase-DNA-binding protein 4 (CHD4) and inhibits viral promoter activation. CHD4 is known to regulate cell differentiation by preventing enhancers from activating promoters. Here, we identified a putative CHD4 inhibitor peptide (VGN73) from the LANA sequence corresponding to the LANA-CHD4 interaction surface. The VGN73 interacts with CHD4 at its PHD domain with a dissociation constant (KD) of 14 nM. Pre-treatment with VGN73 enhanced monocyte differentiation into macrophages and globally altered the repertoire of activated genes in U937 cells. Furthermore, the introduction of the peptide into the cancer cells induced caspase-mediated CHD4 cleavage, triggered cell death, and inhibited tumor growth in a xenograft mouse model. The VGN73 may facilitate cell differentiation therapy.
{"title":"A LANA peptide inhibits tumor growth by inducing CHD4 protein cleavage and triggers cell death","authors":"Hiroki Miura , Kang-Hsin Wang , Tomoki Inagaki , Frank Chuang , Michiko Shimoda , Chie Izumiya , Tadashi Watanabe , Ryan R. Davis , Clifford G. Tepper , Somayeh Komaki , Ken-ichi Nakajima , Ashish Kumar , Yoshihiro Izumiya","doi":"10.1016/j.chembiol.2024.10.003","DOIUrl":"10.1016/j.chembiol.2024.10.003","url":null,"abstract":"<div><div>Kaposi’s sarcoma-associated herpesvirus (KSHV) establishes a latent infection, and viral genes are poised to be transcribed in the latent chromatin. In the poised chromatins, KSHV latency-associated nuclear antigen (LANA) interacts with cellular chromodomain-helicase-DNA-binding protein 4 (CHD4) and inhibits viral promoter activation. CHD4 is known to regulate cell differentiation by preventing enhancers from activating promoters. Here, we identified a putative CHD4 inhibitor peptide (VGN73) from the LANA sequence corresponding to the LANA-CHD4 interaction surface. The VGN73 interacts with CHD4 at its PHD domain with a dissociation constant (K<sub>D</sub>) of 14 nM. Pre-treatment with VGN73 enhanced monocyte differentiation into macrophages and globally altered the repertoire of activated genes in U937 cells. Furthermore, the introduction of the peptide into the cancer cells induced caspase-mediated CHD4 cleavage, triggered cell death, and inhibited tumor growth in a xenograft mouse model. The VGN73 may facilitate cell differentiation therapy.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 1909-1925.e7"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1016/j.chembiol.2024.08.004
Dae Gyu Kim , Minkyoung Kim , Ja-il Goo , Jiwon Kong , Dipesh S. Harmalkar , Qili Lu , Aneesh Sivaraman , Hossam Nada , Sreenivasulu Godesi , Hwayoung Lee , Mo Eun Song , Eunjoo Song , Kang-Hyun Han , Woojin Kim , Pilhan Kim , Won Jun Choi , Chang Hoon Lee , Sunkyung Lee , Yongseok Choi , Sunghoon Kim , Kyeong Lee
AIMP2-DX2 (hereafter DX2) is an oncogenic variant of aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) that mediates tumorigenic interactions with various factors involved in cancer. Reducing the levels of DX2 can effectively inhibit tumorigenesis. We previously reported that DX2 can be degraded through Siah1-mediated ubiquitination. In this study, we identified a compound, SDL01, which enhanced the interaction between DX2 and Siah1, thereby facilitating the ubiquitin-dependent degradation of DX2. SDL01 was found to bind to the pocket surrounding the N-terminal flexible region and GST domain of DX2, causing a conformational change that stabilized its interaction with Siah1. Our findings demonstrate that protein-protein interactions (PPIs) can be modulated through chemically induced conformational changes.
{"title":"Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination","authors":"Dae Gyu Kim , Minkyoung Kim , Ja-il Goo , Jiwon Kong , Dipesh S. Harmalkar , Qili Lu , Aneesh Sivaraman , Hossam Nada , Sreenivasulu Godesi , Hwayoung Lee , Mo Eun Song , Eunjoo Song , Kang-Hyun Han , Woojin Kim , Pilhan Kim , Won Jun Choi , Chang Hoon Lee , Sunkyung Lee , Yongseok Choi , Sunghoon Kim , Kyeong Lee","doi":"10.1016/j.chembiol.2024.08.004","DOIUrl":"10.1016/j.chembiol.2024.08.004","url":null,"abstract":"<div><div>AIMP2-DX2 (hereafter DX2) is an oncogenic variant of aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) that mediates tumorigenic interactions with various factors involved in cancer. Reducing the levels of DX2 can effectively inhibit tumorigenesis. We previously reported that DX2 can be degraded through Siah1-mediated ubiquitination. In this study, we identified a compound, SDL01, which enhanced the interaction between DX2 and Siah1, thereby facilitating the ubiquitin-dependent degradation of DX2. SDL01 was found to bind to the pocket surrounding the <em>N</em>-terminal flexible region and GST domain of DX2, causing a conformational change that stabilized its interaction with Siah1. Our findings demonstrate that protein-protein interactions (PPIs) can be modulated through chemically induced conformational changes.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 1958-1968.e8"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142161122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1016/j.chembiol.2024.06.012
Metin Cetin , Ozge Saatci , Abdol-Hossein Rezaeian , Chintada Nageswara Rao , Chad Beneker , Kukkamudi Sreenivas , Harrison Taylor , Breanna Pederson , Ioulia Chatzistamou , Brian Buckley , Susan Lessner , Peggi Angel , Campbell McInnes , Ozgur Sahin
Lysyl oxidase (LOX) is upregulated in highly stiff aggressive tumors, correlating with metastasis, resistance, and worse survival; however, there are currently no potent, safe, and orally bioavailable small molecule LOX inhibitors to treat these aggressive desmoplastic solid tumors in clinics. Here we discovered bi-thiazole derivatives as potent LOX inhibitors by robust screening of drug-like molecules combined with cell/recombinant protein-based assays. Structure-activity relationship analysis identified a potent lead compound (LXG6403) with ∼3.5-fold specificity for LOX compared to LOXL2 while not inhibiting LOXL1 with a competitive, time- and concentration-dependent irreversible mode of inhibition. LXG6403 shows favorable pharmacokinetic properties, globally changes ECM/collagen architecture, and reduces tumor stiffness. This leads to better drug penetration, inhibits FAK signaling, and induces ROS/DNA damage, G1 arrest, and apoptosis in chemoresistant triple-negative breast cancer (TNBC) cell lines, PDX organoids, and in vivo. Overall, our potent and tolerable bi-thiazole LOX inhibitor enhances chemoresponse in TNBC, the deadliest breast cancer subtype.
{"title":"A highly potent bi-thiazole inhibitor of LOX rewires collagen architecture and enhances chemoresponse in triple-negative breast cancer","authors":"Metin Cetin , Ozge Saatci , Abdol-Hossein Rezaeian , Chintada Nageswara Rao , Chad Beneker , Kukkamudi Sreenivas , Harrison Taylor , Breanna Pederson , Ioulia Chatzistamou , Brian Buckley , Susan Lessner , Peggi Angel , Campbell McInnes , Ozgur Sahin","doi":"10.1016/j.chembiol.2024.06.012","DOIUrl":"10.1016/j.chembiol.2024.06.012","url":null,"abstract":"<div><div>Lysyl oxidase (LOX) is upregulated in highly stiff aggressive tumors, correlating with metastasis, resistance, and worse survival; however, there are currently no potent, safe, and orally bioavailable small molecule LOX inhibitors to treat these aggressive desmoplastic solid tumors in clinics. Here we discovered bi-thiazole derivatives as potent LOX inhibitors by robust screening of drug-like molecules combined with cell/recombinant protein-based assays. Structure-activity relationship analysis identified a potent lead compound (LXG6403) with ∼3.5-fold specificity for LOX compared to LOXL2 while not inhibiting LOXL1 with a competitive, time- and concentration-dependent irreversible mode of inhibition. LXG6403 shows favorable pharmacokinetic properties, globally changes ECM/collagen architecture, and reduces tumor stiffness. This leads to better drug penetration, inhibits FAK signaling, and induces ROS/DNA damage, G1 arrest, and apoptosis in chemoresistant triple-negative breast cancer (TNBC) cell lines, PDX organoids, and <em>in vivo</em>. Overall, our potent and tolerable bi-thiazole LOX inhibitor enhances chemoresponse in TNBC, the deadliest breast cancer subtype.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 1926-1941.e11"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141746559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1016/j.chembiol.2024.10.006
Alexandria N. Van Scoyk , Orlando Antelope , Donald E. Ayer , Randall T. Peterson , Anthony D. Pomicter , Shawn C. Owen , Michael W. Deininger
Lysine acylation can direct protein function, localization, and interactions. Sirtuins deacylate lysine toward maintaining cellular homeostasis, and their aberrant expression contributes to the pathogenesis of multiple conditions, including cancer. Measuring sirtuins’ activity is essential to exploring their potential as therapeutic targets, but accurate quantification is challenging. We developed “SIRTify”, a high-sensitivity assay for measuring sirtuin activity in vitro and in vivo. SIRTify is based on a split-version of the NanoLuc luciferase consisting of a truncated, catalytically inactive N-terminal moiety (LgBiT) that complements with a high-affinity C-terminal peptide (p86) to form active luciferase. Acylation of two lysines within p86 disrupts binding to LgBiT and abates luminescence. Deacylation by sirtuins reestablishes p86 and restores binding, generating a luminescence signal proportional to sirtuin activity. Measurements accurately reflect reported sirtuin specificity for lysine-acylations and confirm the effects of sirtuin modulators. SIRTify quantifies lysine deacylation dynamics and may be adaptable to monitoring additional post-translational modifications.
{"title":"Bioluminescence assay of lysine deacylase sirtuin activity","authors":"Alexandria N. Van Scoyk , Orlando Antelope , Donald E. Ayer , Randall T. Peterson , Anthony D. Pomicter , Shawn C. Owen , Michael W. Deininger","doi":"10.1016/j.chembiol.2024.10.006","DOIUrl":"10.1016/j.chembiol.2024.10.006","url":null,"abstract":"<div><div>Lysine acylation can direct protein function, localization, and interactions. Sirtuins deacylate lysine toward maintaining cellular homeostasis, and their aberrant expression contributes to the pathogenesis of multiple conditions, including cancer. Measuring sirtuins’ activity is essential to exploring their potential as therapeutic targets, but accurate quantification is challenging. We developed “SIRT<em>ify</em>”, a high-sensitivity assay for measuring sirtuin activity <em>in vitro</em> and <em>in vivo</em>. SIRT<em>ify</em> is based on a split-version of the NanoLuc luciferase consisting of a truncated, catalytically inactive N-terminal moiety (LgBiT) that complements with a high-affinity C-terminal peptide (p86) to form active luciferase. Acylation of two lysines within p86 disrupts binding to LgBiT and abates luminescence. Deacylation by sirtuins reestablishes p86 and restores binding, generating a luminescence signal proportional to sirtuin activity. Measurements accurately reflect reported sirtuin specificity for lysine-acylations and confirm the effects of sirtuin modulators. SIRT<em>ify</em> quantifies lysine deacylation dynamics and may be adaptable to monitoring additional post-translational modifications.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 2002-2014.e4"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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