Article
Biochemistry & Molecular Biology
Huixin Liang, Wei Wang, Fugui Zhu, Shuqiang Chen, Dan Liu, Chunquan Sheng
Summary: A series of novel bis-evodiamine derivatives inspired by the antitumor natural product evodiamine were synthesized, and they exhibited potent antitumor activity. Notably, compound 13b effectively inhibited the proliferation and migration of HCT116 cells. Mechanistic studies further revealed that compound 13b induced apoptosis in HCT116 cells and arrested the cell cycle at the G2/M phase. Therefore, compound 13b represents a promising lead compound for the discovery of novel antitumor agents.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Organic
Saibin Zhu, Yeji Wang, Zhongqing Wen, Yanwen Duan, Yong Huang
Summary: The study revealed that Huanglongmycin congener 14 exhibited stronger cytotoxicity against tested cancer cells, and highlighted the critical role of the C-7 ethyl group of 14 in its binding to the DNA-topoisomerase I complex.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Moataz A. Shaldam, Hadia Almahli, Andrea Angeli, Rehab Mustafa Badi, Eman F. Khaleel, Abdelrahman I. Zain-Alabdeen, Zainab M. Elsayed, Eslam B. Elkaeed, Rofaida Salem, Claudiu T. Supuran, Wagdy M. Eldehna, Haytham O. Tawfik
Summary: New isatin-based sulphonamides were synthesized as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. The most potent derivatives showed strong VEGFR-2 inhibitory effect but failed to inhibit relevant CA isoforms. Two derivatives were further tested for their impact on cell cycle disturbance and apoptotic potential. Molecular modelling analyses were conducted to assess the binding mode and stability of the target compounds.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Honggang Xiang, Mi Zhou, Yan Li, Lu Zhou, Renxiao Wang
Summary: Autophagy is a cellular process that involves the engulfment and degradation of proteins and organelles through protein-protein interactions. Targeting selective regulation of these interactions provides a new opportunity for autophagy regulation with lower risk of off-target effects. This article provides background knowledge on critical protein-protein interactions in autophagy and reviews successful attempts in discovering regulators targeting these interactions. It also discusses successful strategies and existing limitations in this field.
ACTA PHARMACEUTICA SINICA B
(2023)
Review
Biochemistry & Molecular Biology
Nadja B. B. Cech, Nicholas H. H. Oberlies
Summary: Many researchers in the natural product sciences have the dream of discovering a successful drug, but for Dr. Monroe Wall and Dr. Mansukh Wani, their efforts led to the discovery of two new drugs, taxol and camptothecin, which continue to be critical in cancer therapy today.
NATURAL PRODUCT REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Matic Proj, Martina Hrast, Gregor Bajc, Rok Frlan, Anze Meden, Matej Butala, Stanislav Gobec
Summary: Bacterial resistance is a growing threat to healthcare systems, highlighting the urgent need for discovering new antibacterial agents. Using fragment-based drug discovery, researchers targeted a bacterial enzyme Ddl and identified a potential inhibitor with promising development prospects.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Lixin Zhou, Xiuquan Ye, Kaizhen Wang, Hongtao Shen, Tianyu Wang, Xiangyu Zhang, Sheng Jiang, Yibei Xiao, Kuojun Zhang
Summary: Hematopoietic progenitor kinase 1 (HPK1), a negative regulator of T-cell receptor (TCR) signaling, has been identified as a promising target for tumor immunotherapy. In this study, a series of structurally novel diaminotriazine carboxamides were designed and synthesized as inhibitors of HPK1 kinase. Compound 15b showed more potent inhibitory activity against HPK1 kinase than the previously developed compound 11d. Compound 15b also demonstrated significant efficacy in inducing immune response and inhibiting tumor growth in mice, making it a promising lead for the development of effective HPK1 inhibitors.
BIOORGANIC CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Hewen Jiang, Zongkang Zhang, Yuanyuan Yu, Hang Yin Chu, Sifan Yu, Shanshan Yao, Ge Zhang, Bao-Ting Zhang
Summary: This article reviews the currently available or under study DKK1 inhibitors and discusses future research prospects.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Chemistry, Medicinal
Ting Guo, Shutao Ma
Summary: The treatment of cancer faces challenges with currently approved tyrosine kinase inhibitors, as they are becoming less effective in complex cancers and contributing to chemotherapy resistance. Multitargeted tyrosine kinase inhibitors are more advantageous in therapeutic effects and have become a hotspot in antitumor drug research.
Article
Chemistry, Medicinal
Vajja Krishna Rao, Anvesh Ashtam, Dulal Panda, Sankar K. Guchhait
Summary: This study investigated the discovery of new tubulin polymerization inhibitors using a natural product-inspired strategy and incorporation of an NP-privileged motif. The synthesized compounds showed significant antiproliferative effects in breast cancer cells, and one compound demonstrated potent inhibitory activity on tubulin polymerization and induction of cell death.
Article
Chemistry, Multidisciplinary
Lili Ai, Tianhuan Peng, Yingying Li, Hailan Kuai, Yingyu Sima, Minhui Su, Dan Wang, Qiuxia Yang, Xue-Qiang Wang, Weihong Tan
Summary: This study describes the development of a novel dual-targeting circular aptamer that can recognize two different biomarkers on living cells, enhancing the recognition of target cells. This improvement not only boosts the binding and internalization abilities of the aptamer, but also expands its recognition spectrum to different leukemia cells.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Zhenxi Niu, Shuli Ma, Lei Zhang, Qibing Liu, Shengnan Zhang
Summary: A novel series of quinazoline derivatives were designed and synthesized, and compound 18 showed potent antitumor activity and selectivity against MGC-803 cells, with low micromolar cytotoxicity and inhibition of tumor growth.
Article
Chemistry, Multidisciplinary
Hongyue Yu, Yan Yu, Runfeng Lin, Minchao Liu, Qiaoyu Zhou, Mengli Liu, Liang Chen, Wenxing Wang, Ahmed A. Elzatahry, Dongyuan Zhao, Xiaomin Li
Summary: A camouflaged virus-like nanocarrier with a transformable rough surface composed of a mesoporous SiO2 nanoparticle and an acid-responsive polymer is reported. Under normal pH conditions, the spikes on the nanocarrier are hidden by the polymer shell, inhibiting non-specific strong nano-bio interactions. In an acidic tumor microenvironment, the nanocarrier sheds the polymer camouflage to expose its rough surface, improving retention ability and endocytosis efficiency. The rationally designed nanocarrier exhibits extended blood circulation time and enhanced tumor accumulation due to its dynamically variable rough surface.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Maria V. Babak, Kai Ren Chong, Peter Rapta, Markella Zannikou, Hui Min Tang, Lisa Reichert, Meng Rui Chang, Vladimir Kushnarev, Petra Heffeter, Samuel M. Meier-Menches, Zhi Chiaw Lim, Jian Yu Yap, Angela Casini, Irina V. Balyasnikova, Wee Han Ang
Summary: The study developed a novel drug complex 3met which can induce deadly metabolic catastrophe in triple-negative breast cancer, reducing tumor burden and significantly improving treatment outcomes.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Ling Yu, Jian-hui Li, Ju Zhu, You-de Wang, Zhi-wei Yan, Li-ying Zhang, Shuai Li
Summary: This study reported 22 novel erythrina derivatives as PARP-1 inhibitors with antitumor activities and explored their mechanism of action. Compound 11b exhibited better anti-proliferative effects against A549 cells and had low toxicity. Flow cytometry assays and molecular docking studies revealed that compound 11b induced apoptosis and effectively reduced the formation of PAR.
Article
Biochemistry & Molecular Biology
Daniel Mueller-Klieser, Thorsten Berg
Summary: Stafia-1 is presented as a compound that selectively inhibits the transcription factor STAT5a, while being selective over STAT5b. Researchers have outlined a synthetic strategy for asymmetrically substituted m-terphenyl phosphates to address the asymmetric STAT5a binding site more specifically. The synthetic methodology and activity analysis provide insights into the structure-activity relationships of m-terphenyl phosphates as selective STAT5a inhibitors.
Article
Biochemistry & Molecular Biology
Lisa Kolano, Daniel Knappe, Angela Berg, Thorsten Berg, Ralf Hoffmann
Summary: Proline-rich antimicrobial peptides (PrAMPs) show promise as potential treatments for infections caused by high-priority human pathogens. Their mechanism of action involves passive diffusion across the outer membrane, active transport through the inner membrane, and inhibition of protein biosynthesis by blocking the ribosome's exit tunnel. However, in vitro data on ribosomal binding and bacterial uptake may not be sufficient to accurately predict the antibacterial activity of PrAMPs, as other factors can also influence their efficacy, such as membrane permeability, transport mechanisms, and secondary targets.
Article
Chemistry, Multidisciplinary
Juliane Brauer, Marina Moetzing, Corinna Groest, Ralf Hoffmann, Thorsten Berg
Summary: This study presents a new method for the synthesis of large, chemically uniform bioactive molecules inside living cells using cyclononynes, addressing the issues of low cell permeability and oral bioavailability commonly associated with high-affinity inhibitors of large protein-protein interactions. The synthesized inhibitor achieved vastly accelerated templated reactions in aqueous environments, demonstrating the potential of cyclononynes for the development of effective inhibitors.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Multidisciplinary Sciences
Valeria Napolitano, Charlotte A. Softley, Artur Blat, Vishal C. Kalel, Kenji Schorpp, Till Siebenmorgen, Kamyar Hadian, Ralf Erdmann, Michael Sattler, Grzegorz M. Popowicz, Grzegorz Dubin
Summary: Trypanosomiasis is a life-threatening infection and requires new therapeutic approaches. In this study, the researchers identified the PEX5-PTS1 interaction as a key player in the import of glycolytic enzymes in Trypanosoma. They developed a fluorescence polarization-based method and successfully identified small molecule inhibitors that can disrupt this interaction and inhibit parasite growth in cell culture.
SCIENTIFIC REPORTS
(2022)
Article
Nanoscience & Nanotechnology
Nian Liu, Patrick O'Connor, Vipul Gujrati, Pia Anzenhofer, Uwe Klemm, Karin Kleigrewe, Michael Sattler, Oliver Plettenburg, Vasilis Ntziachristos
Summary: This study introduces CR880-based nanoparticles for deep tissue optoacoustic imaging and photothermal therapy. These nanoparticles exhibit high optoacoustic generation efficiency and photostability, and can be visualized in tumors with high image contrast. Moreover, they have high photothermal conversion efficiency for effective tumor elimination.
Article
Biochemistry & Molecular Biology
Stefan Gaussmann, Mohanraj Gopalswamy, Hamed Kooshapur, Chen Zheng, Iris Antes, Eva Hambruch, Wolfgang Schliebs, Ralf Erdmann, Michael Sattler
Summary: The cycling import receptor PEX5 and its binding partner PEX14 play important roles in the peroxisomal import machinery. They recognize cargo proteins carrying a peroxisomal targeting signal type 1 (PTS1) and dock at the peroxisomal membrane. This study characterizes the recognition of (di)aromatic peptides motifs by PEX14 and identifies key features involved in the interaction. The findings provide a refined consensus motif for high affinity binding to PEX14 and suggest conservation of the (di)aromatic peptide recognition by PEX14 in other species.
BIOLOGICAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Valeria Napolitano, Piotr Mroz, Monika Marciniak, Vishal C. Kalel, Charlotte A. Softley, Julian D. Janna Olmos, Bettina G. Tippler, Kenji Schorpp, Sarah Rioton, Tony Froehlich, Oliver Plettenburg, Kamyar Hadian, Ralf Erdmann, Michael Sattler, Grzegorz M. Popowicz, Maciej Dawidowski, Grzegorz Dubin
Summary: Trypanosomiases are neglected tropical diseases caused by Trypanosoma (sub)species. The inhibition of the PEX5-PEX14 protein-protein interaction has shown potential as a lethal treatment for Trypanosoma. Researchers have developed a novel compound scaffold that inhibits PEX5-PEX14 PPI and has demonstrated trypanocidal activity in cell-based assays.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Dilip Narayanan, Kim T. Tran, Jakob S. Pallesen, Sara M. O. Solbak, Yuting Qin, Elina Mukminova, Martina Luchini, Kristina O. Vasilyeva, Dorleta Gonzalez Chichon, Georgia Goutsiou, Cecilie Poulsen, Nanna Haapanen, Grzegorz M. Popowicz, Michael Sattler, David Olagnier, Michael Gajhede, Anders Bach
Summary: This study utilized fluorescence polarization, thermal shift assay, and surface plasmon resonance to screen 2500 small-molecule fragments, resulting in the identification of 28 high-priority hits. The binding modes of these hits were validated through saturation transfer difference NMR, providing insights into the development of novel small-molecule Keap1-Nrf2 protein-protein interaction inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Philipp Keil, Alexander Wulf, Nitin Kachariya, Samira Reuscher, Kristin Huhn, Ivan Silbern, Janine Altmuller, Mario Keller, Ralf Stehle, Kathi Zarnack, Michael Sattler, Henning Urlaub, Katja Straesser
Summary: RNA-binding proteins (RBPs) control RNA metabolism through protein-RNA and protein-protein interactions. In this study, we identified in vivo RNA crosslinks in nuclear mRNP components and functionally analyzed the Npl3 protein. Mutations in the RNA recognition motifs (RRMs) and linker region of Npl3 revealed distinct functions of different RNA-binding domains. Importantly, a linker mutation impaired mRNP assembly, revealing a previously unknown function of Npl3. This integrative analysis can be applied to study RBPs in other RNA metabolic processes.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemical Research Methods
Joel Roca-Martinez, Hrishikesh Dhondge, Michael Sattler, Wim Vranken
Summary: This study analyzed the interactions between RNA recognition motif (RRM) and RNA sequences through computational analysis, and identified the main binding mode and relevant amino acids. A predictor called RRMScorer was developed to predict the binding between RRM and RNA based on their sequences. This tool can be used to identify new potential RNA targets and design mutants with modified RNA binding capabilities.
PLOS COMPUTATIONAL BIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Enrica Zanuttigh, Kevork Derderian, Miriam A. Guera, Arie Geerlof, Ivano Di Meo, Chiara Cavestro, Stefan Hempfling, Stephanie Ortiz-Collazos, Mario Mauthe, Tomasz Kmiec, Eugenia Cammarota, Maria Carla Panzeri, Thomas Klopstock, Michael Sattler, Juliane Winkelmann, Ana C. Messias, Arcangela Iuso
Summary: "Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a neurodegenerative disorder caused by mutations in the C19orf12 gene. This study found that there were no consistent alterations in mitochondrial functions or cellular signaling in MPAN fibroblasts, but autophagy initiation was consistently impaired. Furthermore, several potential therapeutic compounds for MPAN were identified through screening autophagy modulators."
Article
Chemistry, Physical
Nicola Calonaci, Mattia Bernetti, Alisha Jones, Michael Sattler, Giovanni Bussi
Summary: In this study, we used atomistic molecular dynamics simulations to investigate the binding of RNA with SHAPE reagents. We proposed and tested the hypothesis that cooperative effects can lead to concentration-dependent reactivity. Our simulations and analysis of experimental data support the idea that cooperative binding can indeed affect the reactivity of SHAPE experiments.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Multidisciplinary Sciences
Komal Soni, Pravin Kumar Ankush Jagtap, Santiago Martinez-Lumbreras, Sophie Bonnal, Arie Geerlof, Ralf Stehle, Bernd Simon, Juan Valcarcel, Michael Sattler
Summary: This study reveals the structural mechanism of RNA-binding protein RBM5, which cooperates through multiple RNA-binding domains to recognize specific target RNA sequences and regulate alternative splicing of genes implicated in cancer.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Valeria Napolitano, Agnieszka Dabrowska, Kenji Schorpp, Andre Mourao, Emilia Barreto-Duran, Malgorzata Benedyk, Pawel Botwina, Stefanie Brandner, Mark Bostock, Yuliya Chykunova, Anna Czarna, Grzegorz Dubin, Tony Froehlich, Michael Hoelscher, Malwina Jedrysik, Alex Matsuda, Katarzyna Owczarek, Magdalena Pachota, Oliver Plettenburg, Jan Potempa, Ina Rothenaigner, Florian Schlauderer, Klaudia Slysz, Artur Szczepanski, Kristin Greve-Isdahl Mohn, Bjorn Blomberg, Michael Sattler, Kamyar Hadian, Grzegorz Maria Popowicz, Krzysztof Pyrc
Summary: Acriflavine has been identified as a potent inhibitor of viral replication in SARS-CoV-2 and other betacoronaviruses, with potential for immediate use in clinical trials and future outbreaks.
CELL CHEMICAL BIOLOGY
(2022)
Article
Computer Science, Interdisciplinary Applications
Zhonghua Xia, Pavel Karpov, Grzegorz Popowicz, Michael Sattler, Igor Tetko
Summary: Small-molecule drug design aims to identify inhibitors that can specifically bind to an enzyme's active site. Traditional methods rely on static structures to identify binding pockets, but small molecules can induce the opening of dynamic pockets. This study assessed the features in molecules that can induce cryptic pocket opening and developed a model to design inducers for undruggable proteins.
