journal
https://read.qxmd.com/read/38508197/protac-mediated-degradation-of-hiv-1-nef-efficiently-restores-cell-surface-cd4-and-mhc-i-expression-and-blocks-hiv-1-replication
#1
JOURNAL ARTICLE
Lori A Emert-Sedlak, Colin M Tice, Haibin Shi, John J Alvarado, Sherry T Shu, Allen B Reitz, Thomas E Smithgall
The HIV-1 Nef accessory factor enhances the viral life cycle in vivo, promotes immune escape of HIV-infected cells, and represents an attractive antiretroviral drug target. However, Nef lacks enzymatic activity and an active site, complicating traditional occupancy-based drug development. Here we describe the development of proteolysis targeting chimeras (PROTACs) for the targeted degradation of Nef. Nef-binding compounds, based on an existing hydroxypyrazole core, were coupled to ligands for ubiquitin E3 ligases via flexible linkers...
March 13, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38508196/chemical-immunology-recent-advances-in-tool-development-and-applications
#2
REVIEW
Yujie Shi, Eleanor E Bashian, Yingqin Hou, Peng Wu
Immunology was one of the first biological fields to embrace chemical approaches. The development of new chemical approaches and techniques has provided immunologists with an impressive arsenal of tools to address challenges once considered insurmountable. This review focuses on advances at the interface of chemistry and immunobiology over the past two decades that have not only opened new avenues in basic immunological research, but also revolutionized drug development for the treatment of cancer and autoimmune diseases...
March 13, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38492573/selective-targeting-of-plasmodium-falciparum-hsp90-disrupts-the-26s-proteasome
#3
JOURNAL ARTICLE
Christopher R Mansfield, Baiyi Quan, Michael E Chirgwin, Benjamin Eduful, Philip F Hughes, Gaëlle Neveu, Kayla Sylvester, Daniel H Ryan, Björn F C Kafsack, Timothy A J Haystead, James W Leahy, Michael C Fitzgerald, Emily R Derbyshire
The molecular chaperone heat shock protein 90 (Hsp90) has an essential but largely undefined role in maintaining proteostasis in Plasmodium falciparum, the most lethal malaria parasite. Herein, we identify BX-2819 and XL888 as potent P. falciparum (Pf)Hsp90 inhibitors. Derivatization of XL888's scaffold led to the development of Tropane 1, as a PfHsp90-selective binder with nanomolar affinity. Hsp90 inhibitors exhibit anti-Plasmodium activity against the liver, asexual blood, and early gametocyte life stages...
March 13, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38513646/flex-genetically-encodable-enzymatic-fluorescence-signal-amplification-using-engineered-peroxidase
#4
JOURNAL ARTICLE
Nirmali Sharma, Minkyo Jung, Pratyush Kumar Mishra, Ji Young Mun, Hyun-Woo Rhee
Fluorescent tagging of biomolecules enables their sensitive detection during separation and determining their subcellular location. In this context, peroxidase-based reactions are actively utilized for signal amplification. To harness this potential, we developed a genetically encodable enzymatic fluorescence signal amplification method using APEX (FLEX). We synthesized a fluorescent probe, Jenfluor triazole (JFT1), which effectively amplifies and restricts fluorescence signals under fixed conditions, enabling fluorescence-based detection of subcellularly localized electron-rich metabolites...
March 8, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38460516/a-proximity-labeling-based-orthogonal-trap-strategy-identifies-hdac8-promotes-cell-motility-by-modulating-cortactin-acetylation
#5
JOURNAL ARTICLE
Yepei Huang, Guijin Zhai, Yun Fu, Yanan Li, Yong Zang, Yu Lin, Kai Zhang
It is a challenge for the traditional affinity methods to capture transient interactions of enzyme-post-translational modification (PTM) substrates in vivo. Herein we presented a strategy termed proximity labeling-based orthogonal trap approach (ProLORT), relying upon APEX2-catalysed proximity labeling and an orthogonal trap pipeline as well as quantitative proteomics to directly investigate the transient interactome of enzyme-PTM substrates in living cells. As a proof of concept, ProLORT allows for robust evaluation of a known HDAC8 substrate, histone H3K9ac...
March 6, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38442710/a-sterol-analog-inhibits-hedgehog-pathway-by-blocking-cholesterylation-of-smoothened
#6
JOURNAL ARTICLE
Yuan-Bin Liu, Li-Ming He, Ming Sun, Wen-Jun Luo, Zi-Cun Lin, Zhi-Ping Qiu, Yu-Liang Zhang, Ao Hu, Jie Luo, Wen-Wei Qiu, Bao-Liang Song
The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation...
February 28, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38428418/metabolic-rewiring-and-communication-in-cancer-immunity
#7
REVIEW
Nicole M Chapman, Hongbo Chi
The immune system shapes tumor development and progression. Although immunotherapy has transformed cancer treatment, its overall efficacy remains limited, underscoring the need to uncover mechanisms to improve therapeutic effects. Metabolism-associated processes, including intracellular metabolic reprogramming and intercellular metabolic crosstalk, are emerging as instructive signals for anti-tumor immunity. Here, we first summarize the roles of intracellular metabolic pathways in controlling immune cell function in the tumor microenvironment...
February 26, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38402621/allosteric-inhibition-of-trna-synthetase-gln4-by-n-pyrimidinyl-%C3%AE-thiophenylacrylamides-exerts-highly-selective-antifungal-activity
#8
JOURNAL ARTICLE
Emily Puumala, David Sychantha, Elizabeth Lach, Shawn Reeves, Sunna Nabeela, Meea Fogal, AkshatKumar Nigam, Jarrod W Johnson, Alán Aspuru-Guzik, Rebecca S Shapiro, Priya Uppuluri, Subha Kalyaanamoorthy, Jakob Magolan, Luke Whitesell, Nicole Robbins, Gerard D Wright, Leah E Cowen
Candida species are among the most prevalent causes of systemic fungal infections, which account for ∼1.5 million annual fatalities. Here, we build on a compound screen that identified the molecule N-pyrimidinyl-β-thiophenylacrylamide (NP-BTA), which strongly inhibits Candida albicans growth. NP-BTA was hypothesized to target C. albicans glutaminyl-tRNA synthetase, Gln4. Here, we confirmed through in vitro amino-acylation assays NP-BTA is a potent inhibitor of Gln4, and we defined how NP-BTA arrests Gln4's transferase activity using co-crystallography...
February 20, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38382532/cyp7b1-mediated-25-hydroxycholesterol-degradation-maintains-quiescence-activation-balance-and-improves-therapeutic-potential-of-mesenchymal-stem-cells
#9
JOURNAL ARTICLE
Zhaoqiang Zhang, Zepeng Su, Zhikun Li, Jinteng Li, Wenhui Yu, Guiwen Ye, Jiajie Lin, Yunshu Che, Peitao Xu, Yipeng Zeng, Yanfeng Wu, Huiyong Shen, Zhongyu Xie
Stem cells remain quiescent in vivo and become activated in response to external stimuli. However, the mechanism regulating the quiescence-activation balance of bone-marrow-derived mesenchymal stem cells (BM-MSCs) is still unclear. Herein, we demonstrated that CYP7B1 was the common critical molecule that promoted activation and impeded quiescence of BM-MSCs under inflammatory stimulation. Mechanistically, CYP7B1 degrades 25-hydroxycholesterol (25-HC) into 7α,25-dihydroxycholesterol (7α,25-OHC), which alleviates the quiescence maintenance effect of 25-HC through Notch3 signaling pathway activation...
February 16, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38335967/identification-of-differential-biological-activity-and-synergy-between-the-parp-inhibitor-rucaparib-and-its-major-metabolite
#10
JOURNAL ARTICLE
Huabin Hu, Carme Serra, Wenjie Zhang, Aurora Scrivo, Irene Fernández-Carasa, Antonella Consiglio, Alvaro Aytes, Miguel Angel Pujana, Amadeu Llebaria, Albert A Antolin
The (poly)pharmacology of drug metabolites is seldom comprehensively characterized in drug discovery. However, some drug metabolites can reach high plasma concentrations and display in vivo activity. Here, we use computational and experimental methods to comprehensively characterize the kinase polypharmacology of M324, the major metabolite of the PARP1 inhibitor rucaparib. We demonstrate that M324 displays unique PLK2 inhibition at clinical concentrations. This kinase activity could have implications for the efficacy and safety of rucaparib and therefore warrants further clinical investigation...
February 6, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38320555/the-cyclimids-degron-inspired-cereblon-binders-for-targeted-protein-degradation
#11
JOURNAL ARTICLE
Saki Ichikawa, N Connor Payne, Wenqing Xu, Chia-Fu Chang, Nandini Vallavoju, Spencer Frome, Hope A Flaxman, Ralph Mazitschek, Christina M Woo
Cereblon (CRBN) is an E3 ligase substrate adapter widely exploited for targeted protein degradation (TPD) strategies. However, achieving efficient and selective target degradation is a preeminent challenge with ligands that engage CRBN. Here, we report that the cyclimids, ligands derived from the C-terminal cyclic imide degrons of CRBN, exhibit distinct modes of interaction with CRBN and offer a facile approach for developing potent and selective bifunctional degraders. Quantitative TR-FRET-based characterization of 60 cyclimid degraders in binary and ternary complexes across different substrates revealed that ternary complex binding affinities correlated strongly with cellular degradation efficiency...
January 31, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38309277/anti-tumor-immunotherapy-using-engineered-bacterial-outer-membrane-vesicles-fused-to-lysosome-targeting-chimeras-mediated-by-transferrin-receptor
#12
JOURNAL ARTICLE
Ling-Yan Su, Yang Tian, Qiang Zheng, Yu Cao, Mengyu Yao, Shuangping Wang, Wen Xu, Chuyu Xi, Andrea Clocchiatti, Guangjun Nie, Hejiang Zhou
The lysosome-targeting chimera (LYTAC) approach has shown promise for the targeted degradation of secreted and membrane proteins via lysosomes. However, there have been challenges in design, development, and targeting. Here, we have designed a genetically engineered transferrin receptor (TfR)-mediated lysosome-targeting chimera (TfR-LYTAC) that is efficiently internalized via TfR-mediate endocytosis and targets PD-L1 for lysosomal degradation in cultured cells but not in vivo due to short half-life and poor tumor targeting...
January 30, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38307028/identification-and-characterization-of-a-potent-and-selective-hunk-inhibitor-for-treatment-of-her2-breast-cancer
#13
JOURNAL ARTICLE
Tinslee Dilday, Melissa Abt, Nicole Ramos-Solís, Neetu Dayal, Elizabeth Larocque, Adrian L Oblak, Herman O Sintim, Elizabeth S Yeh
Human epidermal growth factor receptor 2 (HER2)-targeted agents have proven to be effective, however, the development of resistance to these agents has become an obstacle in treating HER2+ breast cancer. Evidence implicates HUNK as an anti-cancer target for primary and resistant HER2+ breast cancers. In this study, a selective inhibitor of HUNK is characterized alongside a phosphorylation event in a downstream substrate of HUNK as a marker for HUNK activity in HER2+ breast cancer. Rubicon has been established as a substrate of HUNK that is phosphorylated at serine (S) 92...
January 25, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38262416/parp-trapping-is-governed-by-the-parp-inhibitor-dissociation-rate-constant
#14
JOURNAL ARTICLE
Angelica A Gopal, Bianca Fernandez, Justin Delano, Ralph Weissleder, J Matthew Dubach
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of cancer drugs that enzymatically inhibit PARP activity at sites of DNA damage. Yet, PARPi function mainly by trapping PARP1 onto DNA with a wide range of potency among the clinically relevant inhibitors. How PARPi trap and why some are better trappers remain unknown. Here, we show trapping occurs primarily through a kinetic phenomenon at sites of DNA damage that correlates with PARPi koff . Our results suggest PARP trapping is not the physical stalling of PARP1 on DNA, rather the high probability of PARP re-binding damaged DNA in the absence of other DNA-binding protein recruitment...
January 20, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38266648/beyond-antibiotic-resistance-the-whib7-transcription-factor-coordinates-an-adaptive-response-to-alanine-starvation-in-mycobacteria
#15
JOURNAL ARTICLE
Nicholas C Poulton, Michael A DeJesus, Vanisha Munsamy-Govender, Mariko Kanai, Cameron G Roberts, Zachary A Azadian, Barbara Bosch, Karl Matthew Lin, Shuqi Li, Jeremy M Rock
Pathogenic mycobacteria are a significant cause of morbidity and mortality worldwide. The conserved whiB7 stress response reduces the effectiveness of antibiotic therapy by activating several intrinsic antibiotic resistance mechanisms. Despite our comprehensive biochemical understanding of WhiB7, the complex set of signals that induce whiB7 expression remain less clear. We employed a reporter-based, genome-wide CRISPRi epistasis screen to identify a diverse set of 150 mycobacterial genes whose inhibition results in constitutive whiB7 expression...
January 9, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38232732/bioorthogonal-click-labeling-of-an-amber-free-hiv-1-provirus-for-in-virus-single-molecule-imaging
#16
JOURNAL ARTICLE
Yuanyun Ao, Jonathan R Grover, Levi Gifford, Yang Han, Guohua Zhong, Revansiddha Katte, Wenwei Li, Rajanya Bhattacharjee, Baoshan Zhang, Stephanie Sauve, Wenyi Qin, Dibya Ghimire, Md Anzarul Haque, James Arthos, Mahmoud Moradi, Walther Mothes, Edward A Lemke, Peter D Kwong, Gregory B Melikyan, Maolin Lu
Structural dynamics of human immunodeficiency virus 1 (HIV-1) envelope (Env) glycoprotein mediate cell entry and facilitate immune evasion. Single-molecule FRET using peptides for Env labeling revealed structural dynamics of Env, but peptide use risks potential effects on structural integrity/dynamics. While incorporating noncanonical amino acids (ncAAs) into Env by amber stop-codon suppression, followed by click chemistry, offers a minimally invasive approach, this has proved to be technically challenging for HIV-1...
January 8, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38183989/an-acyl-coa-thioesterase-is-essential-for-the-biosynthesis-of-a-key-dauer-pheromone-in-c-%C3%A2-elegans
#17
JOURNAL ARTICLE
Subhradeep Bhar, Chi-Su Yoon, Kevin Mai, Jungsoo Han, Dilip V Prajapati, Yuting Wang, Candy L Steffen, Laura S Bailey, Kari B Basso, Rebecca A Butcher
Methyl ketone (MK)-ascarosides represent essential components of several pheromones in Caenorhabditis elegans, including the dauer pheromone, which triggers the stress-resistant dauer larval stage, and the male-attracting sex pheromone. Here, we identify an acyl-CoA thioesterase, ACOT-15, that is required for the biosynthesis of MK-ascarosides. We propose a model in which ACOT-15 hydrolyzes the β-keto acyl-CoA side chain of an ascaroside intermediate during β-oxidation, leading to decarboxylation and formation of the MK...
January 4, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38199037/causes-functions-and-therapeutic-possibilities-of-rna-secondary-structure-ensembles-and-alternative-states
#18
REVIEW
Ritwika Bose, Irfana Saleem, Anthony M Mustoe
RNA secondary structure plays essential roles in encoding RNA regulatory fate and function. Most RNAs populate ensembles of alternatively paired states and are continually unfolded and refolded by cellular processes. Measuring these structural ensembles and their contributions to cellular function has traditionally posed major challenges, but new methods and conceptual frameworks are beginning to fill this void. In this review, we provide a mechanism- and function-centric compendium of the roles of RNA secondary structural ensembles and minority states in regulating the RNA life cycle, from transcription to degradation...
January 3, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38215746/the-interaction-between-nlrp1-and-oxidized-trx1-involves-a-transient-disulfide-bond
#19
JOURNAL ARTICLE
Michael B Geeson, Jeffrey C Hsiao, Lydia P Tsamouri, Daniel P Ball, Daniel A Bachovchin
NLRP1 is an innate immune receptor that detects pathogen-associated signals, assembles into a multiprotein structure called an inflammasome, and triggers a proinflammatory form of cell death called pyroptosis. We previously discovered that the oxidized, but not the reduced, form of thioredoxin-1 directly binds to NLRP1 and represses inflammasome formation. However, the molecular basis for NLRP1's selective association with only the oxidized form of TRX1 has not yet been established. Here, we leveraged AlphaFold-Multimer, site-directed mutagenesis, thiol-trapping experiments, and mass spectrometry to reveal that a specific cysteine residue (C427 in humans) on NLRP1 forms a transient disulfide bond with oxidized TRX1...
January 2, 2024: Cell Chemical Biology
https://read.qxmd.com/read/38194973/discovery-of-a-protac-degrader-for-mettl3-mettl14-complex
#20
JOURNAL ARTICLE
Wenhao Du, Yuting Huang, Xiaoai Chen, Yue Deng, Yaoliang Sun, Hong Yang, Qiongyu Shi, Feifei Wu, Guobin Liu, He Huang, Jian Ding, Xun Huang, Shilin Xu
N6 -methyladenosine (m6 A) methylation is the most abundant type of RNA modification that is mainly catalyzed by the METTL3-METTL14 methyltransferase complex. This complex has been linked to multiple cancers and is considered a promising therapeutic target for acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity were developed recently. Here, we present the discovery of WD6305 as the potent and selective proteolysis-targeting chimera (PROTAC) degrader of METTL3-METTL14 complex...
January 2, 2024: Cell Chemical Biology
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