ACS Bio & Med Chem Au最新文献_第3页

Total Synthesis and Microbiological Evaluation of Leopolic Acid A and Analogues 莱奥酚酸 A 及其类似物的全合成和微生物学评价

ACS Bio & Med Chem Au Pub Date : 2024-01-12 DOI: 10.1021/acsbiomedchemau.3c00068

Jamie L. Breunig, M. Alejandro Valdes-Pena, Andrew W. Ratchford and Joshua G. Pierce*,

引用次数: 0

Proteases Involved in Leader Peptide Removal during RiPP Biosynthesis 参与 RiPP 生物合成过程中头端肽去除的蛋白酶

ACS Bio & Med Chem Au Pub Date : 2023-12-13 DOI: 10.1021/acsbiomedchemau.3c00059

Sara M. Eslami, and , Wilfred A. van der Donk*,

{"title":"Proteases Involved in Leader Peptide Removal during RiPP Biosynthesis","authors":"Sara M. Eslami,  and , Wilfred A. van der Donk*, ","doi":"10.1021/acsbiomedchemau.3c00059","DOIUrl":"10.1021/acsbiomedchemau.3c00059","url":null,"abstract":"Ribosomally synthesized and post-translationally modified peptides (RiPPs) have received much attention in recent years because of their promising bioactivities and the portability of their biosynthetic pathways. Heterologous expression studies of RiPP biosynthetic enzymes identified by genome mining often leave a leader peptide on the final product to prevent toxicity to the host and to allow the attachment of a genetically encoded affinity purification tag. Removal of the leader peptide to produce the mature natural product is then carried out in vitro with either a commercial protease or a protease that fulfills this task in the producing organism. This review covers the advances in characterizing these latter cognate proteases from bacterial RiPPs and their utility as sequence-dependent proteases. The strategies employed for leader peptide removal have been shown to be remarkably diverse. They include one-step removal by a single protease, two-step removal by two dedicated proteases, and endoproteinase activity followed by aminopeptidase activity by the same protease. Similarly, the localization of the proteolytic step varies from cytoplasmic cleavage to leader peptide removal during secretion to extracellular leader peptide removal. Finally, substrate recognition ranges from highly sequence specific with respect to the leader and/or modified core peptide to nonsequence specific mechanisms.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"4 1","pages":"20–36"},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.3c00059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138581457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Small-Molecule Inhibitors of the m7G-RNA Writer METTL1 m7G-RNA 写入器 METTL1 的小分子抑制剂

ACS Bio & Med Chem Au Pub Date : 2023-12-12 DOI: 10.1021/acsbiomedchemau.3c00030

Francesco Nai, Maria Paula Flores Espinoza, Annalisa Invernizzi, Pablo Andrés Vargas-Rosales, Olga Bobileva, Marcin Herok and Amedeo Caflisch*,

引用次数: 0

Deciphering the Synthetic and Refolding Strategy of a Cysteine-Rich Domain in the Tumor Necrosis Factor Receptor (TNF-R) for Racemic Crystallography Analysis and d-Peptide Ligand Discovery 破译肿瘤坏死因子受体（TNF-R）富半胱氨酸结构域的合成和重折叠策略，以进行消旋结晶学分析和多肽配体的发现

ACS Bio & Med Chem Au Pub Date : 2023-12-11 DOI: 10.1021/acsbiomedchemau.3c00060

Alexander J. Lander, Yifu Kong, Yi Jin*, Chuanliu Wu* and Louis Y. P. Luk*,

{"title":"Deciphering the Synthetic and Refolding Strategy of a Cysteine-Rich Domain in the Tumor Necrosis Factor Receptor (TNF-R) for Racemic Crystallography Analysis and d-Peptide Ligand Discovery","authors":"Alexander J. Lander, Yifu Kong, Yi Jin*, Chuanliu Wu* and Louis Y. P. Luk*, ","doi":"10.1021/acsbiomedchemau.3c00060","DOIUrl":"10.1021/acsbiomedchemau.3c00060","url":null,"abstract":"Many cell-surface receptors are promising targets for chemical synthesis because of their critical roles in disease development. This synthetic approach enables investigations by racemic protein crystallography and ligand discovery by mirror-image methodologies. However, due to their complex nature, the chemical synthesis of a receptor can be a significant challenge. Here, we describe the chemical synthesis and folding of a central, cysteine-rich domain of the cell-surface receptor tumor necrosis factor 1 which is integral to binding of the cytokine TNF-α, namely, TNFR-1 CRD2. Racemic protein crystallography at 1.4 Å confirmed that the native binding conformation was preserved, and TNFR-1 CRD2 maintained its capacity to bind to TNF-α (KD ≈ 7 nM). Encouraged by this discovery, we carried out mirror-image phage display using the enantiomeric receptor mimic and identified a d-peptide ligand for TNFR-1 CRD2 (KD = 1 μM). This work demonstrated that cysteine-rich domains, including the central domains, can be chemically synthesized and used as mimics for investigations.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"4 1","pages":"68–76"},"PeriodicalIF":0.0,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.3c00060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138567038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Diazirine Photoprobes for the Identification of Vancomycin-Binding Proteins 万古霉素结合蛋白的重氮嗪光探针鉴定

ACS Bio & Med Chem Au Pub Date : 2023-11-20 DOI: 10.1021/acsbiomedchemau.3c00067

Photis Rotsides, Paula J. Lee, Nakoa Webber, Kimberly C. Grasty, Joris Beld and Patrick J. Loll*,

{"title":"Diazirine Photoprobes for the Identification of Vancomycin-Binding Proteins","authors":"Photis Rotsides, Paula J. Lee, Nakoa Webber, Kimberly C. Grasty, Joris Beld and Patrick J. Loll*, ","doi":"10.1021/acsbiomedchemau.3c00067","DOIUrl":"10.1021/acsbiomedchemau.3c00067","url":null,"abstract":"Vancomycin’s interactions with cellular targets drive its antimicrobial activity and also trigger expression of resistance against the antibiotic. Interaction partners for vancomycin have previously been identified using photoaffinity probes, which have proven to be useful tools for exploring vancomycin’s interactome. This work seeks to develop diazirine-based vancomycin photoprobes that display enhanced specificity and bear fewer chemical modifications as compared to previous photoprobes. Using proteins fused to vancomycin’s main cell-wall target, d-alanyl-d-alanine, we used mass spectrometry to show that these photoprobes specifically label known vancomycin-binding partners within minutes. In a complementary approach, we developed a Western-blot strategy targeting the vancomycin adduct of the photoprobes, eliminating the need for affinity tags and simplifying the analysis of photolabeling reactions. Together, the probes and identification strategy provide a novel and streamlined pipeline for identifying vancomycin-binding proteins.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"4 2","pages":"86–94"},"PeriodicalIF":0.0,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.3c00067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138528976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Effect of Deuteration and Homologation of the Lactam Ring of Nirmatrelvir on Its Biochemical Properties and Oxidative Metabolism 尼马特瑞韦内酰胺环的氘化和同源化对其生化特性和氧化代谢的影响

ACS Bio & Med Chem Au Pub Date : 2023-11-15 DOI: 10.1021/acsbiomedchemau.3c00039

Elena Arutyunova, Alexandr Belovodskiy*, Pu Chen, Muhammad Bashir Khan, Michael Joyce, Holly Saffran, Jimmy Lu, Zoe Turner, Bing Bai, Tess Lamer, Howard S. Young, John C. Vederas, D. Lorne Tyrrell, M. Joanne Lemieux* and James A. Nieman,

{"title":"The Effect of Deuteration and Homologation of the Lactam Ring of Nirmatrelvir on Its Biochemical Properties and Oxidative Metabolism","authors":"Elena Arutyunova, Alexandr Belovodskiy*, Pu Chen, Muhammad Bashir Khan, Michael Joyce, Holly Saffran, Jimmy Lu, Zoe Turner, Bing Bai, Tess Lamer, Howard S. Young, John C. Vederas, D. Lorne Tyrrell, M. Joanne Lemieux* and James A. Nieman, ","doi":"10.1021/acsbiomedchemau.3c00039","DOIUrl":"10.1021/acsbiomedchemau.3c00039","url":null,"abstract":"This study explores the relationship between structural alterations of nirmatrelvir, such as homologation and deuteration, and metabolic stability of newly synthesized derivatives. We developed a reliable synthetic protocol toward dideutero-nirmatrelvir and its homologated analogues with high isotopic incorporation. Deuteration of the primary metabolic site of nirmatrelvir provides a 3-fold improvement of its human microsomal stability but is accompanied by an increased metabolism rate at secondary sites. Homologation of the lactam ring allows the capping group modification to decrease and delocalize the molecule’s lipophilicity, reducing the metabolic rate at secondary sites. The effect of deuteration was less pronounced for the 6-membered lactam than for its 5-membered analogue in human microsomes, but the trend is reversed in the case of mouse microsomes. X-ray data revealed that the homologation of the lactam ring favors the orientation of the drug’s nitrile warhead for interaction with the catalytic sulfur of the SARS-CoV-2 Mpro, improving its binding. Comparable potency against SARS-CoV-2 Mpro from several variants of concern and selectivity over human cysteine proteases cathepsin B, L, and S was observed for the novel deuterated/homologated derivative and nirmatrelvir. Synthesized compounds displayed a large interspecies variability in hamster, rat, and human hepatocyte stability assays. Overall, we aimed to apply a rational approach in changing the physicochemical properties of the drug to refine its biochemical and biological parameters.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"3 6","pages":"528–541"},"PeriodicalIF":0.0,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.3c00039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138528979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Conflicting Interfacial Electrostatic Interactions as a Design Principle to Modulate Long-Range Interdomain Communication 将相互冲突的界面静电相互作用作为调制远距离域间通讯的设计原则

ACS Bio & Med Chem Au Pub Date : 2023-11-07 DOI: 10.1021/acsbiomedchemau.3c00047

Adithi Kannan, Dhruv Kumar Chaurasiya and Athi N. Naganathan*,

{"title":"Conflicting Interfacial Electrostatic Interactions as a Design Principle to Modulate Long-Range Interdomain Communication","authors":"Adithi Kannan, Dhruv Kumar Chaurasiya and Athi N. Naganathan*, ","doi":"10.1021/acsbiomedchemau.3c00047","DOIUrl":"10.1021/acsbiomedchemau.3c00047","url":null,"abstract":"The extent and molecular basis of interdomain communication in multidomain proteins, central to understanding allostery and function, is an open question. One simple evolutionary strategy could involve the selection of either conflicting or favorable electrostatic interactions across the interface of two closely spaced domains to tune the magnitude of interdomain connectivity. Here, we study a bilobed domain FF34 from the eukaryotic p190A RhoGAP protein to explore one such design principle that mediates interdomain communication. We find that while the individual structural units in wild-type FF34 are marginally coupled, they exhibit distinct intrinsic stabilities and low cooperativity, manifesting as slow folding. The FF3-FF4 interface harbors a frustrated network of highly conserved electrostatic interactions─a charge troika─that promotes the population of multiple, decoupled, and non-native structural modes on a rugged native landscape. Perturbing this network via a charge-reversal mutation not only enhances stability and cooperativity but also dampens the fluctuations globally and speeds up the folding rate by at least an order of magnitude. Our work highlights how a conserved but nonoptimal network of interfacial electrostatic interactions shapes the native ensemble of a bilobed protein, a feature that could be exploited in designing molecular systems with long-range connectivity and enhanced cooperativity.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"4 1","pages":"53–67"},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.3c00047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135539894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Intrinsically Disordered Ku Protein-Derived Cell-Penetrating Peptides 内在无序 Ku 蛋白衍生的细胞穿透肽

ACS Bio & Med Chem Au Pub Date : 2023-10-31 DOI: 10.1021/acsbiomedchemau.3c00032

Biswanath Maity, Hariharan Moorthy and Thimmaiah Govindaraju*,

引用次数: 0

Delineating the Role of GxxxG Motif in Amyloidogenesis: A New Perspective in Targeting Amyloid-Beta Mediated AD Pathogenesis 阐明 GxxxG 基因在淀粉样蛋白生成中的作用：针对淀粉样蛋白-β介导的注意力缺失症发病机制的新视角

ACS Bio & Med Chem Au Pub Date : 2023-10-30 DOI: 10.1021/acsbiomedchemau.3c00055

Dibakar Sarkar, and , Anirban Bhunia*,

引用次数: 0

The C-Terminal of NaV1.7 Is Ubiquitinated by NEDD4L NaV1.7 的 C 端被 NEDD4L 泛素化

ACS Bio & Med Chem Au Pub Date : 2023-10-13 DOI: 10.1021/acsbiomedchemau.3c00031

Katharine M. Wright, Hanjie Jiang, Wendy Xia, Michael B. Murphy, Tatiana N. Boronina, Justin N. Nwafor, HyoJeon Kim, Akunna M. Iheanacho, P. Aitana Azurmendi, Robert N. Cole, Philip A. Cole and Sandra B. Gabelli*,

{"title":"The C-Terminal of NaV1.7 Is Ubiquitinated by NEDD4L","authors":"Katharine M. Wright, Hanjie Jiang, Wendy Xia, Michael B. Murphy, Tatiana N. Boronina, Justin N. Nwafor, HyoJeon Kim, Akunna M. Iheanacho, P. Aitana Azurmendi, Robert N. Cole, Philip A. Cole and Sandra B. Gabelli*, ","doi":"10.1021/acsbiomedchemau.3c00031","DOIUrl":"10.1021/acsbiomedchemau.3c00031","url":null,"abstract":"NaV1.7, the neuronal voltage-gated sodium channel isoform, plays an important role in the human body’s ability to feel pain. Mutations within NaV1.7 have been linked to pain-related syndromes, such as insensitivity to pain. To date, the regulation and internalization mechanisms of the NaV1.7 channel are not well known at a biochemical level. In this study, we perform biochemical and biophysical analyses that establish that the HECT-type E3 ligase, NEDD4L, ubiquitinates the cytoplasmic C-terminal (CT) region of NaV1.7. Through in vitro ubiquitination and mass spectrometry experiments, we identify, for the first time, the lysine residues of NaV1.7 within the CT region that get ubiquitinated. Furthermore, binding studies with an NEDD4L E3 ligase modulator (ubiquitin variant) highlight the dynamic partnership between NEDD4L and NaV1.7. These investigations provide a framework for understanding how NEDD4L-dependent regulation of the channel can influence the NaV1.7 function.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"3 6","pages":"516–527"},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.3c00031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135857986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0