Article
Biochemistry & Molecular Biology
Severin Lechner, Martin Ian P. Malgapo, Christian Graetz, Raphael R. Steimbach, Agnes Baron, Patrick Ruether, Simon Nadal, Carmen Stumpf, Christina Loos, Xin Ku, Polina Prokofeva, Ludwig Lautenbacher, Tino Heimburg, Vivian Wuerf, Chen Meng, Mathias Wilhelm, Wolfgang Sippl, Karin Kleigrewe, Josch K. Pauling, Karl Kramer, Aubry K. Miller, Michael W. Pfaffl, Maurine E. Linder, Bernhard Kuster, Guillaume Medard
Summary: This study used a quantitative chemical proteomics assay to investigate the target landscape of 53 drugs that target HDAC. The results questioned the selectivity of some widely-used molecules and revealed the influence of HDAC complex composition on drug potency. Additionally, the study identified MBLAC2 as a frequent off-target of hydroxamate drugs and suggested it as a potential target for drug discovery due to its involvement in extracellular vesicle accumulation.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Sourav Chowdhury, Daniel C. Zielinski, Christopher Dalldorf, Joao V. Rodrigues, Bernhard O. Palsson, Eugene I. Shakhnovich
Summary: Elucidating intracellular drug targets is a challenging problem, and machine learning analysis of omics data has shown promise but faces difficulties in identifying specific targets. In this study, a hierarchic workflow combining metabolomics data analysis and growth rescue experiments was developed to prioritize drug candidates. The study successfully identified HPPK (folK) as an off-target of the antibiotic compound CD15-3 through machine learning, metabolic modelling, and protein structural similarity analysis. This research highlights the potential of integrating machine learning methods with mechanistic analyses to improve drug target finding workflows.
NATURE COMMUNICATIONS
(2023)
Review
Immunology
Junna Jiao, Zhuangwei Lv, Yurong Wang, Liye Fan, Angang Yang
Summary: Activation-induced cytidine deaminase (AID) plays a crucial role in promoting B cell diversification through somatic hypermutation (SHM) and class switch recombination (CSR). Apart from its physiological function of humoral immune response, AID has been linked to the initiation and progression of lymphomas. This review proposes an alternative role for AID and explores its off-target effects in regulating tumorigenesis.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Felix P. Mayer, Marco Niello, Daniela Cintulova, Spyridon Sideromenos, Julian Maier, Yang Li, Simon Bulling, Oliver Kudlacek, Klaus Schicker, Hideki Iwamoto, Fei Deng, Jinxia Wan, Marion Holy, Rania Katamish, Walter Sandtner, Yulong Li, Daniela D. Pollak, Randy D. Blakely, Marko D. Mihovilovic, Michael H. Baumann, Harald H. Sitte
Summary: Increasing extracellular levels of serotonin can ameliorate symptoms of depression and anxiety-related disorders. The study found that certain ring-substituted cathinones show preference for the release of serotonin and exert 5-HT-associated effects in behavioral models. These compounds have low abuse liability and potential for adverse events.
MOLECULAR PSYCHIATRY
(2023)
Article
Multidisciplinary Sciences
Xiaolong Cheng, Zexu Li, Ruocheng Shan, Zihan Li, Shengnan Wang, Wenchang Zhao, Han Zhang, Lumen Chao, Jian Peng, Teng Fei, Wei Li
Summary: A major challenge in the application of the CRISPR-Cas13d system is accurately predicting its guide-dependent on-target and off-target effects. In this study, researchers used CRISPR-Cas13d proliferation screens and developed a deep learning model called DeepCas13 to predict on-target activity based on guide sequences and secondary structures. DeepCas13 outperformed existing methods in predicting the efficiency of guides targeting both protein-coding and non-coding RNAs.
NATURE COMMUNICATIONS
(2023)
Article
Pharmacology & Pharmacy
Alessandro Giuliani, Stefano Fais
Summary: The crisis in drug discovery involves various epistemological and scientific aspects, and drug repurposing is one proposed solution. The microenvironment could serve as an ideal target for directing the off-target effects of known drugs.
Review
Biotechnology & Applied Microbiology
Congting Guo, Xiaoteng Ma, Fei Gao, Yuxuan Guo
Summary: Gene editing involves precise changes to specific nucleic acid sequences. The CRISPR/Cas9 system has revolutionized gene editing, making it efficient, convenient, and programmable. However, off-target effects remain a major concern, leading to unexpected alterations in the genome. Various methods have been developed to detect and mitigate these off-target effects, advancing the precision of CRISPR/Cas9 derivatives. This review summarizes these technological advancements and discusses the challenges in managing off-target effects for future gene therapy.
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
(2023)
Article
Multidisciplinary Sciences
Yini Wang, Bowen Zhong, Caixia Xu, Dongdong Zhan, Songhao Zhao, Hongxing Wu, Mingwei Liu, Xiaoling Lan, Danni Cai, Qian Ding, Biao Zheng, Jiong Lan, Qiang Lv, Yi Wang, Jun Qin
Summary: KRAS inhibitor AMG510 covalently modifies the G12C residue and inhibits the KRAS/G12C function. A comprehensive study characterizes the on-target modification and off-targets of AMG510, identifying over 300 off-target sites. AMG510 modifies proteins involved in nucleocytoplasmic transport, oxidative stress response, adaptive immune system, and glycolysis, and inhibits the enzyme activity of ALDOA and induces NRF2 accumulation independent of KRAS/G12C mutation. The study provides valuable insights into the potential toxicological side effects of AMG510.
Article
Chemistry, Medicinal
Arash Sadri
Summary: Target-based drug discovery, although dominant, lacks a comprehensive evaluation of its efficiency, as demonstrated by a manual review of 32000 articles and patents spanning 150 years. Only 9.4% of small-molecule drugs have been discovered through target-based assays, and their therapeutic effects cannot be solely attributed to their intended targets due to off-target mechanisms. This suggests that a reductionist approach may be the cause of the current productivity crisis, and an evidence-based approach using tools like artificial intelligence and machine learning may enhance efficiency.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Anna Dimoula, Dimitrios Fotellis, Evmorfia Aivalioti, Dimitrios Delialis, Alexia Polissidis, Raphael Patras, Nikolaos Kokras, Kimon Stamatelopoulos
Summary: Depression is considered a risk factor for cardiovascular disease, and successful antidepressant treatment may reduce the risk of cardiovascular events. Selective serotonin reuptake inhibitors (SSRIs) have been shown to have beneficial effects on vascular inflammation, endothelial function, and arterial stiffening. However, it is challenging to distinguish the direct beneficial effects of antidepressants on endothelial health from the overall improvement in depression in clinical studies.
Review
Urology & Nephrology
Antonio De Pascalis, Giuseppe Cianciolo, Irene Capelli, Giuliano Brunori, Gaetano La Manna
Summary: SGLT2 inhibitors are a new class of antidiabetic drugs that not only lower blood sugar but also potentially improve renal and cardiovascular outcomes. However, the mechanisms of their effect on sodium balance remain unclear, requiring further research.
JOURNAL OF NEPHROLOGY
(2021)
Article
Immunology
Prisca Benedicto-Matambo, Julie E. Bines, Chikondi Malamba-Banda, Isaac T. Shawa, Kayla Barnes, Arox W. Kamng'ona, Daniel Hungerford, Kondwani C. Jambo, Miren Iturriza-Gomara, Nigel A. Cunliffe, Katie L. Flanagan, Khuzwayo C. Jere
Summary: Live-attenuated vaccines have been shown to reduce deaths and hospitalizations associated with diarrhea in children and may provide protection against other infections as well. The off-target effects of vaccination are thought to be mediated by modified innate and adaptive immunity. However, it remains unclear whether rotavirus vaccines can also reduce non targeted gastrointestinal infections.
Review
Plant Sciences
Julia Neumeier, Gunter Meister
Summary: SiRNAs and miRNAs function differently in RNAi, with siRNAs directly cleaving target RNAs while miRNAs inhibit translation followed by exonucleolytic decay. However, siRNAs can also lead to miRNA-like off-target effects.
FRONTIERS IN PLANT SCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Martin Pacesa, Chun-Han Lin, Antoine Clery, Aakash Saha, Pablo R. Arantes, Katja Bargsten, Matthew J. Irby, Frederic H. -T. Allain, Giulia Palermo, Peter Cameron, Paul D. Donohoue, Martin Jinek
Summary: The crystallographic structures of Cas9 bound to off-target substrates reveal that noncanonical base-pairing interactions within the guide:off-target heteroduplex enable off-target binding. Single-nucleotide deletions in off-target substrates are accommodated by base skipping or multiple noncanonical base pairs. PAM-distal mismatches result in duplex unpairing and induce a conformational change in the Cas9 REC lobe. These insights contribute to the improved rational design of guide RNAs and off-target prediction algorithms.
Article
Multidisciplinary Sciences
Romano Strobelt, Julia Adler, Nir Paran, Yfat Yahalom-Ronen, Sharon Melamed, Boaz Politi, Ziv Shulman, Dominik Schmiedel, Yosef Shaul
Summary: The drug imatinib has been found to robustly decrease SARS-CoV-2 infection by inhibiting the viral entry process. It acts through a non-target mechanism by inhibiting membrane fusion and endocytosis of the virus, making it a promising therapeutic drug for COVID-19.
SCIENTIFIC REPORTS
(2022)
Article
Cell Biology
Curtis A. Thorne, Ina W. Chen, Laura E. Sanman, Melanie H. Cobb, Lani F. Wu, Steven J. Altschuler
DEVELOPMENTAL CELL
(2018)
Article
Multidisciplinary Sciences
Clinton A. Taylor, Kevin W. Cormier, Shannon E. Keenan, Svetlana Earnest, Steve Stippec, Chonlarat Wichaidit, Yu-Chi Juang, Junmei Wang, Stanislav Y. Shvartsman, Elizabeth J. Goldsmith, Melanie H. Cobb
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2019)
Article
Multidisciplinary Sciences
Xu-Dong Wang, Rongkuan Hu, Qing Ding, Trisha K. Savage, Kenneth E. Huffman, Noelle Williams, Melanie H. Cobb, John D. Minna, Jane E. Johnson, Yonghao Yu
NATURE COMMUNICATIONS
(2019)
Article
Multidisciplinary Sciences
Michael Kalwat, Melanie H. Cobb
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
(2019)
Article
Biochemistry & Molecular Biology
Chen Shen, Bin Li, Luisana Astudillo, Murray P. Deutscher, Melanie H. Cobb, Anthony J. Capobianco, Ethan Lee, David J. Robbins
Article
Cell Biology
Michael A. Kalwat, Zhimin Huang, Derk D. Binns, Kathleen McGlynn, Melanie H. Cobb
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2020)
Article
Cell Biology
Zhenan Liu, Joonho Yoon, Chonlarat Wichaidit, Ankita B. Jaykumar, Hashem A. Dbouk, Addie E. Embry, Liping Liu, Joel M. Henderson, Audrey N. Chang, Melanie H. Cobb, Richard Tyler Miller
Summary: Calcineurin inhibitors can protect podocytes and glomerular capillaries by preserving podocyte cytoskeletal structure, preventing injury in many glomerular diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Endocrinology & Metabolism
Michael A. Kalwat, Donalyn Scheuner, Karina Rodrigues-Dos-Santos, Decio L. Eizirik, Melanie H. Cobb
Summary: Pancreatic beta cells play a crucial role in maintaining glucose homeostasis by producing insulin and adapting to increased secretion demands. The unfolded protein response of the endoplasmic reticulum is a key mechanism used by beta cells to cope with the demands for insulin production. Failure of compensatory mechanisms may contribute to the development of diabetes.
Article
Oncology
Ankita B. Jaykumar, Ji-Ung Jung, Pravat Kumar Parida, Tuyen T. Dang, Chonlarat Wichaidit, Ashari Rashmi Kannangara, Svetlana Earnest, Elizabeth J. Goldsmith, Gray W. Pearson, Srinivas Malladi, Melanie H. Cobb
Summary: The protein kinase WNK1 has been identified as a key player in promoting migration and invasion of breast cancer cells, with its inhibition showing promising results in reducing metastasis. Depletion or inhibition of WNK1 was found to suppress AXL expression, a tyrosine kinase involved in metastasis. These findings suggest that targeting WNK1 may provide a new therapeutic avenue for invasive breast cancers.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Biochemical Research Methods
Xu-Dong Wang, Chiho Kim, Yajie Zhang, Smita Rindhe, Melanie H. Cobb, Yonghao Yu
Summary: Resistance to targeted MAPK pathway inhibition presents a challenge in cancer treatment, with alterations in cholesterol metabolism potentially influencing tumor adaptive responses to pathway inhibitors. Targeting cholesterol in combination with MAPK pathway inhibitors could enhance treatment efficacy in tumors with hyperactive MAPK signaling.
JOURNAL OF PROTEOME RESEARCH
(2021)
Article
Cell Biology
Ji-Ung Jung, Anwesha B. Ghosh, Svetlana Earnest, Staci L. Deaton, Melanie H. Cobb
Summary: The protein kinase WNK1 is involved in maintaining cellular ion homeostasis and its accumulation can lead to familial hypertension. This study investigates the degradation pathways of WNK1 and identifies UBR5 as a regulator of WNK1 protein stability that leads to lysosomal degradation.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Clinton A. Taylor, Kevin W. Cormier, Ana Martin-Vega, Svetlana Earnest, Steve Stippec, Chonlarat Wichaidit, Melanie H. Cobb
Summary: The most frequent ERK2 mutation in cancers, E322K, is located in the common docking (CD) site, affecting its binding with activators, inactivating phosphatases, and substrates. Another mutation, D321N, also affects the CD site but less frequently. These gain-of-function mutations have been found to have subtle differences in behavior, such as increased nuclear retention and disrupted dimer interface.
Article
Multidisciplinary Sciences
Ji-Ung Jung, Melanie H. Cobb
Summary: The protein kinase WNK1 influences the trafficking and actin polymerization of membrane proteins. This study discovered a connection between WNK1 and TRIM27, which regulates endosomal actin polymerization. Depletion of WNK1 disrupted WASH ubiquitination and endosomal actin polymerization, affecting endosomal trafficking. Depletion of WNK1 or TRIM27 increased the degradation of EGFR in cancer cells.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Wang Yuan, Yi M. Weaver, Svetlana Earnest, Clinton A. Taylor, Melanie H. Cobb, Benjamin P. Weaver
Summary: The authors found that the pool of non-phosphorylated p38 MAPK can modulate signaling to control growth, lysosome formation, and neuronal integrity. By altering the stoichiometry of non-phospho-p38, they enhanced PMK-1 signaling to promote tissue integrity and longevity. Their findings suggest that reducing the reservoir of non-phospho-p38 can enhance signaling without hyper-activation of stress response during aging.
NATURE COMMUNICATIONS
(2023)
Review
Biochemistry & Molecular Biology
Ana Martin-Vega, Melanie H. Cobb
Summary: The RAS-ERK pathway is crucial for various biological processes and its aberrant activation is implicated in diseases such as cancer. This review focuses on the structure, activation, regulation, and mutational frequency of the pathway, with an emphasis on ERK1/2. The significance of scaffold proteins in kinase localization and interaction dynamics is highlighted, along with potential therapeutic approaches in this field.
