ACS Chemical Biology最新文献_第6页

Decoding Protein–Peptide Interactions Using a Large, Target-Agnostic Yeast Surface Display Library 解码蛋白质-肽相互作用使用一个大的，目标不可知的酵母表面显示库。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-13 DOI: 10.1021/acschembio.5c00265

Joseph D. Hurley, Irina Shlosman, Megha Lakshminarayan, Ziyuan Zhao, Hong Yue, Radosław P. Nowak, Eric S. Fischer and Andrew C. Kruse*,

{"title":"Decoding Protein–Peptide Interactions Using a Large, Target-Agnostic Yeast Surface Display Library","authors":"Joseph D. Hurley, Irina Shlosman, Megha Lakshminarayan, Ziyuan Zhao, Hong Yue, Radosław P. Nowak, Eric S. Fischer and Andrew C. Kruse*, ","doi":"10.1021/acschembio.5c00265","DOIUrl":"10.1021/acschembio.5c00265","url":null,"abstract":"Protein–peptide interactions underlie key biological processes and are commonly utilized in biomedical research and therapeutic discovery. It is often desirable to identify peptide sequence properties that confer high-affinity binding to a target protein. However, common approaches to such characterization are typically low throughput and sample only regions of sequence space near an initial hit. To overcome these challenges, we built a yeast surface display library representing ∼6.1 × 109 unique peptides. We then performed screens against diverse protein targets, including two antibodies, an E3 ubiquitin ligase, and an essential membrane-bound bacterial enzyme. In each case, we observed motifs that appear to drive peptide binding, and we identified multiple novel, high-affinity clones. These results highlight the library’s utility as a robust and versatile tool for discovering peptide ligands and for characterizing protein–peptide binding interactions more generally. To enable further studies, we will make the library freely available upon request.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 9","pages":"2120–2133"},"PeriodicalIF":3.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843772","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

Selectivity Profiling of Bromodomain PROTACs Using Chemical Inducers of Proximity DNA-Encoded Library Screening 邻近dna编码文库筛选化学诱导剂对溴域PROTACs的选择性分析。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-12 DOI: 10.1021/acschembio.5c00413

Yuen Ting Chow, Bingqi Tong, Zher Yin Tan, Antonin Tutter, Zhihan Nan, Patricia A. Horton, Michael J. Romanowski, Frédéric J. Zécri, Stuart L. Schreiber and Shuang Liu*,

{"title":"Selectivity Profiling of Bromodomain PROTACs Using Chemical Inducers of Proximity DNA-Encoded Library Screening","authors":"Yuen Ting Chow, Bingqi Tong, Zher Yin Tan, Antonin Tutter, Zhihan Nan, Patricia A. Horton, Michael J. Romanowski, Frédéric J. Zécri, Stuart L. Schreiber and Shuang Liu*, ","doi":"10.1021/acschembio.5c00413","DOIUrl":"10.1021/acschembio.5c00413","url":null,"abstract":"Chemical Inducers of Proximity DNA-Encoded Library (CIP-DEL) screening enables high-throughput discovery of compounds that induce protein–protein interactions, including Proteolysis-Targeting Chimeras (PROTACs). Simultaneous screening of protein paralogs with CIP-DEL allows profiling of compound selectivity and efficient identification of paralog-selective degraders, but such an application has not been reported. Here, we optimized CIP-DEL screening conditions and conducted a von Hippel–Lindau (VHL)-biased CIP-DEL screen with two million DNA-barcoded PROTAC compounds on eight closely related Bromodomain and Extra Terminal domain (BET) bromodomains: BRD2 BD1, BRD2 BD2, BRD3 BD1, BRD3 BD2, BRD4 BD1, BRD4 BD2, BRDT BD1, and BRDT BD2. We observed a marked tendency of compounds to bind the first bromodomain (BD1) preferentially over the second bromodomain (BD2), which contrasts with the predominantly BD2-selective inhibitors reported in the literature. Specifically, our screening approach yielded compound 21–1, which demonstrated promising BRD2 BD1 selectivity in both sequencing data of DEL screening output and in vitro assays. Additionally, normalized relative enrichment selectivity from sequencing data rather than unnormalized absolute enrichment selectivity correlated more closely with experimentally validated selectivity. Overall, we highlight the value of CIP-DEL in profiling PROTAC selectivity, which should be applicable to other protein families with high sequence homologies, where selective degrader discovery remains challenging.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 9","pages":"2266–2276"},"PeriodicalIF":3.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820096","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 Simple, Quick, and Scalable Route to Fluorogenic Ubiquitin and Ubiquitin-Like Protein Substrates for Assessing Activities of Deubiquitinases and Ubiquitin-Like Protein-Specific Proteases 一种简单、快速、可扩展的荧光泛素和泛素样蛋白底物方法，用于评估去泛素酶和泛素样蛋白特异性蛋白酶的活性。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-12 DOI: 10.1021/acschembio.5c00446

Saibal Chanda, Alan Pham, Yifan Shi, Sandeep Atla and Wenshe Ray Liu*,

{"title":"A Simple, Quick, and Scalable Route to Fluorogenic Ubiquitin and Ubiquitin-Like Protein Substrates for Assessing Activities of Deubiquitinases and Ubiquitin-Like Protein-Specific Proteases","authors":"Saibal Chanda, Alan Pham, Yifan Shi, Sandeep Atla and Wenshe Ray Liu*, ","doi":"10.1021/acschembio.5c00446","DOIUrl":"10.1021/acschembio.5c00446","url":null,"abstract":"Ubiquitin (Ub) and ubiquitin-like proteins (UBLs) regulate essential cellular processes as protein modifiers. While Ub signaling is well studied, many UBL pathways remain poorly defined, partly due to the limited availability of suitable UBL substrates. Here, we report the synthesis of fluorogenic Ub-ACA and UBL-ACA probes using the activated cysteine-based protein ligation (ACPL) technique to conjugate recombinant Ub and UBLs containing a C-terminal Gly to Cys mutation with glycyl-2-(7-amino-2-oxo-2H-chromen-4-yl)acetic acid (Gly-ACA), a water-soluble fluorophore. This one-step strategy that allows replacing Cys with Gly-ACA enables simple, quick, and scalable synthesis of Ub-ACA and 11 UBL-ACAs. Five UBL-ACAs represent the first reported fluorogenic substrates for their respective UBLs. Afforded Ub-ACA and 10 UBL-ACAs were demonstrated to be active toward a panel of DUBs or UBL-specific proteases. Notably, SUMO4-ACA was cleaved by SENP1 with efficiency comparable to the other three SUMO-ACA probes despite SUMO4’s distinct structure compared to the other three SUMOs. In human cell lysates, all 12 probes are efficiently cleaved. URM1 has no known proteases. Our results indicate that URM1-specific protease(s) exist in human cells and are yet to be identified. Given their simple and scalable synthesis, these new fluorogenic Ub-ACA and UBL-ACA substrates are highly versatile tools for studying Ub and UBL pathways and drug discovery research.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 9","pages":"2075–2080"},"PeriodicalIF":3.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00446","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design and Characterization of an Anti-Clec9a Antibody Armed with CpG Oligonucleotides To Enable Targeted Delivery of Adjuvant to Cross-Presenting Dendritic Cells 利用CpG寡核苷酸靶向递送佐剂到交叉呈递树突状细胞的抗clec9a抗体的设计和表征。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-12 DOI: 10.1021/acschembio.5c00318

Sayumi Yamazoe*, Keerthi Sadanala, Qian Zhang, Arvind Rajpal, Tim Sproul, Pavel Strop and Miranda Broz,

{"title":"Design and Characterization of an Anti-Clec9a Antibody Armed with CpG Oligonucleotides To Enable Targeted Delivery of Adjuvant to Cross-Presenting Dendritic Cells","authors":"Sayumi Yamazoe*, Keerthi Sadanala, Qian Zhang, Arvind Rajpal, Tim Sproul, Pavel Strop and Miranda Broz, ","doi":"10.1021/acschembio.5c00318","DOIUrl":"10.1021/acschembio.5c00318","url":null,"abstract":"C-type lectin receptor, Clec9a, is a highly specific receptor expressed on cross-presenting conventional dendritic cells (cDC1). This receptor specificity for this rare population of dendritic cells (DCs), combined with their inherent ability to internalize and localize to the endocytic compartment, presents a unique opportunity for targeted delivery of innate immune agonists. By leveraging an anti-Clec9a antibody, we can specifically deliver these agonists to cross-presenting cDCs, thereby enhancing the cross-priming and expansion of tumor-specific cytotoxic T lymphocytes (CTLs). In this study, we detail the design and characterization of innovative bioconjugates composed of a Clec9a-targeting antibody and CpG oligodeoxynucleotides (ODNs), which activate Toll-like receptor 9 (TLR9) expressed by cDC1. These immunomodulatory bioconjugates exhibited significant cellular activity in cross-presentation assays within a coculture system of in vitro generated CD103+ DCs (iCD103 DCs), tumor cells, and antigen specific CTLs, driving robust cross priming. Furthermore, the targeted delivery of ODNs to cDC1 in vivo demonstrated target-dependent activity in a murine vaccination assay. Our findings underscore the potential of Clec9a-targeted bioconjugates as a powerful strategy to enhance antitumor immunity by precisely delivering adjuvants to cross-presenting dendritic cells.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 9","pages":"2180–2190"},"PeriodicalIF":3.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833454","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

Redox Homeostasis as a Key Regulator of Intramolecular Cyclization in Fungal Perylenequinones 氧化还原稳态是真菌苝丙二烯酮分子内环化的关键调控因子。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-12 DOI: 10.1021/acschembio.5c00369

Reema A. Al-Qiam, Firoz S. T. Khan, Huzefa A. Raja, Tyler N. Graf, Cedric J. Pearce, Nicholas H. Oberlies* and Shabnam Hematian*,

{"title":"Redox Homeostasis as a Key Regulator of Intramolecular Cyclization in Fungal Perylenequinones","authors":"Reema A. Al-Qiam, Firoz S. T. Khan, Huzefa A. Raja, Tyler N. Graf, Cedric J. Pearce, Nicholas H. Oberlies* and Shabnam Hematian*, ","doi":"10.1021/acschembio.5c00369","DOIUrl":"10.1021/acschembio.5c00369","url":null,"abstract":"Perylenequinones (PQs) such as hypocrellins and hypomycins are fungal-derived redox-active metabolites with known roles as photosensitizers in the oxidative stress response and applications in photodynamic therapy (PDT). Here, we report that Shiraia sp., a filamentous fungus, can survive and grow under strictly anaerobic (argon) conditions─an unexpected finding for a multicellular eukaryote. Modulating redox homeostasis through chemical reduction and oxygen limitation promotes the intramolecular cyclization of hypocrellins, enhancing hypomycin biosynthesis. Moisture content further influences these transformations, with high water levels favoring keto–enol tautomerization and dry, reducing environments promoting hydride substitution at the peripheral positions. These findings highlight redox modulation as a key driver of perylenequinone metabolism and suggest that PQs may contribute to maintaining redox balance under anaerobic stress, hinting at a broader role in oxygen-independent adaptation in filamentous fungi. This work offers new insights at the interface of redox biology, chemical signaling, and fungal metabolism, with potential implications for the stability and function of PQ-based PDT agents in hypoxic, reducing conditions such as tumor microenvironments.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 9","pages":"2063–2068"},"PeriodicalIF":3.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00369","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activation of N-Formyldipeptide-Masked Prodrugs by Human Peptide Deformylase 人肽去甲酰基酶对n -甲酰基二肽屏蔽前药的激活作用。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-11 DOI: 10.1021/acschembio.5c00298

Raphael Geißen, Okan Yildirim, Maja Köhn, David A. Scheinberg and Derek S. Tan*,

{"title":"Activation of N-Formyldipeptide-Masked Prodrugs by Human Peptide Deformylase","authors":"Raphael Geißen, Okan Yildirim, Maja Köhn, David A. Scheinberg and Derek S. Tan*, ","doi":"10.1021/acschembio.5c00298","DOIUrl":"10.1021/acschembio.5c00298","url":null,"abstract":"Targeted enzyme–prodrug systems deliver an exogenous enzyme to a disease site to generate active drug locally, thus increasing therapeutic efficacy and decreasing systemic toxicity. The majority of such systems have used bacterial enzymes, which are subject to immune recognition and inactivation or clearance in vivo. To address this problem, we report herein the development of a new enzyme–prodrug system that uses a human enzyme, peptide deformylase (PDF), which can be supplied exogenously while the endogenous enzyme is restricted to the mitochondria. The prodrugs feature an optimized masking group comprised of an N-formyldipeptide and a self-immolative m-fluoro-m′-pyridinyl amide (FPA) linker that enables a variety of functional groups to be masked. The mask is designed such that enzymatic deformylation triggers spontaneous dipeptide cyclorelease and linker self-immolation to release the active drug. We demonstrate the effectiveness of this human enzyme–prodrug system in vitro with two cytotoxic drugs, 5′-O-sulfamoyladenosine (AMS) and doxorubicin, masked at distinct functional groups.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 9","pages":"2171–2179"},"PeriodicalIF":3.8,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815263","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

Extending the Peptide/Protein Interaction Paradigm to a Protein/Protein Engagement Model in RiPP Biosynthesis 将多肽/蛋白质相互作用范式扩展到RiPP生物合成中的蛋白质/蛋白质参与模型。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-08 DOI: 10.1021/acschembio.5c00411

Mujeeb A. Wakeel, Elizabeth A. Corbin, Andrew C. McShan and Vinayak Agarwal*,

{"title":"Extending the Peptide/Protein Interaction Paradigm to a Protein/Protein Engagement Model in RiPP Biosynthesis","authors":"Mujeeb A. Wakeel, Elizabeth A. Corbin, Andrew C. McShan and Vinayak Agarwal*, ","doi":"10.1021/acschembio.5c00411","DOIUrl":"10.1021/acschembio.5c00411","url":null,"abstract":"Enzymatic post-translational modification of small precursor peptides generates a wide diversity of bioactive peptidic natural products. The interaction between the precursor peptide and the peptide modifying enzyme relies on recognition of the N-terminal region of the precursor peptide─termed the leader peptide─by the modifying enzyme. In this study, we describe a model for the recognition of atypically long and highly structured nitrile hydratase-like leader peptides (NHLPs) by an azoline forming YcaO cyclodehydratase. Predicated upon the unique structure of NHLPs, the binding model relies on protein/protein interactions between higher-order secondary and tertiary structures of the NHLP and the modifying enzyme. In light of previous findings, we report that different modifying enzymes bind to different molecular surfaces of the NHLPs. These findings illustrate the modularity of different NHLP structural features and how fine-tuning of intermolecular interactions is necessary for efficient catalysis.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 9","pages":"2069–2074"},"PeriodicalIF":3.8,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00411","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CRISPR RiPCA for Investigating eIF4E-m7GpppX Capped mRNA Interactions CRISPR - RiPCA用于研究eIF4E-m7GpppX封顶mRNA相互作用。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-06 DOI: 10.1021/acschembio.5c00471

Gabriela Vega-Hernández, Jesse Duque, Brandon J. C. Klein, Dalia M. Soueid, Jason C. Rech, Hui Wang, Wenhui Zhou and Amanda L. Garner*,

{"title":"CRISPR RiPCA for Investigating eIF4E-m7GpppX Capped mRNA Interactions","authors":"Gabriela Vega-Hernández, Jesse Duque, Brandon J. C. Klein, Dalia M. Soueid, Jason C. Rech, Hui Wang, Wenhui Zhou and Amanda L. Garner*, ","doi":"10.1021/acschembio.5c00471","DOIUrl":"10.1021/acschembio.5c00471","url":null,"abstract":"Post-transcriptional modifications expand the information encoded by an mRNA. These dynamic and reversible modifications are specifically recognized by reader RNA-binding proteins (RBPs), which mediate the regulation of gene expression, RNA processing, localization, stability, and translation. Given their crucial functions, any disruptions in the normal activity of these readers can have significant implications for cellular health. Consequently, the dysregulation of these RBPs has been associated with neurodegenerative disorders, cancers, and viral infections. Therefore, there has been growing interest in targeting reader RBPs as a potential therapeutic strategy since developing molecules that restore proper RNA processing and function may offer a promising avenue for treating diseases. In this work, we coupled our previously established live-cell RNA-protein interaction (RPI) assay, RNA interaction with Protein-mediated Complementation Assay (RiPCA), with CRISPR technology to build a new platform, CRISPR RiPCA. As a model for development, we utilized the interaction of eukaryotic translation initiation factor 4E (eIF4E), a reader RBP that binds to the m7GpppX cap present at the 5′ terminus of coding mRNAs, with an m7G capped RNA substrate. Using eIF4E CRISPR RiPCA, we demonstrate our technology’s potential for measuring on-target activity of inhibitors of the eIF4E RPI of relevance to cancer drug discovery.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 8","pages":"2038–2048"},"PeriodicalIF":3.8,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792938","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

In Vivo Metabolic Labeling with an Isoprenoid Probe Reveals APOE Allele-Specific Differences in the Prenylome 体内代谢标记与类异戊二烯探针揭示APOE等位基因特异性差异在Prenylome。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-06 DOI: 10.1021/acschembio.5c00320

Alexandru M. Petre, Josslen S. Thieschafer, Charuta Palsuledesai, Katie Cornille, Allison Chang, Ling Li* and Mark D. Distefano*,

{"title":"In Vivo Metabolic Labeling with an Isoprenoid Probe Reveals APOE Allele-Specific Differences in the Prenylome","authors":"Alexandru M. Petre, Josslen S. Thieschafer, Charuta Palsuledesai, Katie Cornille, Allison Chang, Ling Li* and Mark D. Distefano*, ","doi":"10.1021/acschembio.5c00320","DOIUrl":"10.1021/acschembio.5c00320","url":null,"abstract":"Prenylation is a ubiquitous process in eukaryotes consisting of the irreversible post-translational modification of proteins through the attachment of a lipophilic isoprenoid moiety to a cysteine residue near their C-terminus. Due to the important functional roles of prenylated proteins, their participation and/or dysregulation has been linked to numerous diseases, including ALS, progeria, cancer, and Alzheimer’s disease (AD). In humans, the APOE4 variant is the greatest known genetic risk factor for late-onset sporadic AD with carriers of two E4 alleles having up to 15 times the risk of developing AD. To begin to unravel the potential relationship between protein prenylation, AD, and APOE variants, it is necessary to study whether different APOE genotypes affect protein prenylation systemically. In the work described here, a methodology for metabolic labeling of prenylated proteins in living mice was first developed. It was then applied to humanized mouse strains that carry human APOE3 or APOE4 alleles. Prenylomic profiling revealed that a number of prenylated proteins were present at higher levels in animals harboring the APOE4 gene compared with those with the APOE3 allele, especially in the liver─a major APOE-producing organ. Importantly, some of these proteins have links to AD neuropathology.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 8","pages":"1951–1961"},"PeriodicalIF":3.8,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787775","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

Systematic Determination of the Impact of Structural Edits on Peptide Accumulation into Mycobacteria 结构编辑对分枝杆菌中肽积累影响的系统测定。

IF 3.8 2区生物学

ACS Chemical Biology Pub Date : 2025-08-01 DOI: 10.1021/acschembio.5c00330

Rachita Dash, Zichen Liu, Irene Lepori, Mahendra D. Chordia, Karl Ocius, Kadie Holsinger, Han Zhang, Ryan Kenyon, Wonpil Im, M. Sloan Siegrist and Marcos M. Pires*,

{"title":"Systematic Determination of the Impact of Structural Edits on Peptide Accumulation into Mycobacteria","authors":"Rachita Dash, Zichen Liu, Irene Lepori, Mahendra D. Chordia, Karl Ocius, Kadie Holsinger, Han Zhang, Ryan Kenyon, Wonpil Im, M. Sloan Siegrist and Marcos M. Pires*, ","doi":"10.1021/acschembio.5c00330","DOIUrl":"10.1021/acschembio.5c00330","url":null,"abstract":"Understanding the factors that influence the accumulation of molecules beyond the mycomembrane of Mycobacterium tuberculosis (Mtb)─the main barrier to accumulation─is essential for developing effective antimycobacterial agents. In this study, we investigated two design principles commonly observed in natural products and mammalian cell-permeable peptides: backbone N-alkylation and macrocyclization. To assess how these structural edits impact molecule accumulation beyond the mycomembrane, we utilized our recently developed Peptidoglycan Accessibility Click-Mediated Assessment (PAC-MAN) assay for live-cell analysis. Our findings provide the first empirical evidence that peptide macrocyclization generally enhances accumulation in mycobacteria, while N-alkylation influences accumulation in a context-dependent manner. We examined these design principles in the context of two peptide antibiotics, tridecaptin A1 and griselimycin, which revealed the roles of N-alkylation and macrocyclization in improving both accumulation and antimicrobial activity against mycobacteria in specific contexts. Together, we present a working model for strategic structural modifications aimed at enhancing the accumulation of molecules past the mycomembrane. More broadly, our results also challenge the prevailing belief in the field that large and hydrophilic molecules, such as peptides, cannot readily traverse the mycomembrane.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 8","pages":"1962–1979"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00330","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0