Article
Biology
Erich Stefan, Richard Obexer, Susanne Hofmann, Khanh Vu Huu, Yichao Huang, Nina Morgner, Hiroaki Suga, Robert Tampe
Summary: The study identified high-affinity peptidic macrocycles through RaPID technology, which selectively bind to the ABC transport complex and display potent inhibitory effects. These macrocycles can block the transporter during conformational switching induced by ATP binding, revealing some fundamental principles of ABC transport.
Review
Pharmacology & Pharmacy
Hayden Peacock, Hiroaki Suga
Summary: Macrocyclic peptides are a promising class of compounds that can engage challenging therapeutic targets, and display technologies like mRNA display are efficient in their discovery. Recent research has also highlighted the incorporation of nonproteinogenic amino acids into macrocyclic peptides.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2021)
Article
Chemistry, Analytical
Zhi-Biao Mai, Zhong-Hua Zhou, Qing-Yu He, Gong Zhang
Summary: This article introduces a contig-scaffolding strategy for high robustness and accuracy in protein sequence assembly. The strategy minimizes bias in the hydrolysis process by integrating multiple unspecific hydrolysis methods and uses a multistep assembly algorithm with error correction. Experimental results demonstrate the effectiveness of this strategy in assembling protein sequences with high coverage and accuracy, even for membrane proteins.
ANALYTICAL CHEMISTRY
(2022)
Article
Gastroenterology & Hepatology
Yawen Lu, Yimeng Chen, Wenxin Hu, Meng Wang, Xiaodong Wen, Jie Yang
Summary: This study aimed to investigate the role and mechanism of acetyl-CoA synthetase 2 (ACSS2) in acute alcohol-induced lipogenesis. The results showed that alcohol challenge induced hepatic lipid deposition and upregulated lipogenic genes, while ACSS2 knockdown blocked histone acetylation and lipogenic gene induction. Ethanol metabolism promoted ACSS2 nuclear import and supported lipogenesis via H3K9 acetylation. In alcohol-feeding mice, liver-specific ACSS2 knockdown blocked the interaction between PCAF and H3K9 and suppressed lipogenic gene induction.
LIVER INTERNATIONAL
(2023)
Article
Multidisciplinary Sciences
Anindya Roy, Lei Shi, Ashley Chang, Xianchi Dong, Andres Fernandez, John C. Kraft, Jing Li, Viet Q. Le, Rebecca Viazzo Winegar, Gerald Maxwell Cherf, Dean Slocum, P. Daniel Poulson, Garrett E. Casper, Mary L. Vallecillo-Zuniga, Jonard Corpuz Valdoz, Marcos C. Miranda, Hua Bai, Yakov Kipnis, Audrey Olshefsky, Tanu Priya, Lauren Carter, Rashmi Ravichandran, Cameron M. Chow, Max R. Johnson, Suna Cheng, McKaela Smith, Catherine Overed-Sayer, Donna K. Finch, David Lowe, Asim K. Bera, Gustavo Matute-Bello, Timothy P. Birkland, Frank DiMaio, Ganesh Raghu, Jennifer R. Cochran, Lance J. Stewart, Melody G. Campbell, Pam M. Van Ry, Timothy Springer, David Baker
Summary: The RGD-binding integrins, alpha v beta 6 and alpha v beta 8, are important therapeutic targets for cancer and fibrosis treatment. This study presents a computational design method for creating RGD-containing miniproteins that specifically bind to a single RGD integrin heterodimer and conformational state. The designed inhibitors show high affinity and stability, and the cryoEM structures confirm their ability to stabilize specific conformational states of the targeted integrins.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Applied
Ravindra S. Phatake, Noy B. Nechmad, Ofer Reany, N. Gabriel Lemcoff
Summary: A selective ring-closing metathesis (RCM) reaction using latent sulfur chelated ruthenium iodide benzylidenes as catalysts, activated by thermal and photochemical stimuli, has been reported. This method enables the formation of large macrocycles with high yields, especially for dienes with one terminal alkene and one internal double bond. For substrates containing two internal double bonds, a sacrificial methylene donor can be used to obtain the desired products.
ADVANCED SYNTHESIS & CATALYSIS
(2022)
Article
Chemistry, Medicinal
Silong Zhai, Yahong Tan, Chengyun Zhang, Christopher John Hipolito, Lulu Song, Cheng Zhu, Youming Zhang, Hongliang Duan, Yizhen Yin
Summary: The study developed an integrated AI framework called PepScaf to assist in the discovery of de novo macrocyclic peptide ligands. By extracting critical scaffold from a vast dataset, over 20 potent peptides were obtained, with the top two displaying exceptional potency with IC50 values of 1.4 nM. This approach offers a viable methodology for efficient macrocyclic peptide discovery and potential time and cost savings, and is also the first report regarding the discovery of macrocyclic peptides against IL-17C/IL-17RE interaction.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Tram Anh Tran, Qing-Jun Zhang, Lei Wang, Christopher Gonzales, Luc Girard, Herman May, Thomas Gillette, Zhi-Ping Liu, Elisabeth D. Martinez
Summary: This study identified the role of Jumonji histone demethylases in the pathogenesis of hypertrophic/dilated cardiomyopathy. Inhibiting the activity of Jumonji demethylases in a mouse model resulted in partial restoration of heart function. This suggests that Jumonji demethylases could be potential therapeutic targets for the treatment of cardiomyopathies.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Chemistry, Analytical
Cuitong He, Catherine C. L. Wong
Summary: Alternative splicing of human genes allows the production of diverse proteoforms, which play crucial roles in normal and disease physiology. However, the discovery of low-abundance proteoforms is limited by current detection methods. This study presents the development of a novel algorithm, CNovo, which outperforms existing algorithms. Furthermore, a semi-de novo sequencing algorithm, SpliceNovo, specifically designed for identifying novel junction peptides, demonstrates higher accuracy than other algorithms. Our results significantly enhance the identification of novel proteoforms through de novo sequencing.
ANALYTICAL CHEMISTRY
(2023)
Article
Chemistry, Analytical
Zhi'ang Chen, Yi Wee Lim, Jin Yong Neo, Rachel Shu Ting Chan, Li Quan Koh, Tsz Ying Yuen, Yee Hwee Lim, Charles W. Johannes, Zachary P. Gates
Summary: A chemical linearization method was applied to sequence synthetic peptide macrocycles, and it was found that linearized macrocycles can be accurately sequenced with lower recall compared to linear peptides. This study demonstrates the potential of using chemical linearization for de novo sequencing.
ANALYTICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Gaurav Bhardwaj, Jacob O'Connor, Stephen Rettie, Yen-Hua Huang, Theresa A. Ramelot, Vikram Khipple Mulligan, Gizem Gokce Alpkilic, Jonathan Palmer, Asim K. Bera, Matthew J. Bick, Maddalena Di Piazza, Xinting Li, Parisa Hosseinzadeh, Timothy W. Craven, Roberto Tejero, Anna Lauko, Ryan Choi, Calina Glynn, Linlin Dong, Robert Griffin, Wesley C. van Voorhis, Jose Rodriguez, Lance Stewart, Gaetano T. Montelione, David Craik, David Baker
Summary: This study investigates the design principles for macrocycle membrane permeability and oral bioavailability using computational design and experimental characterization. The results show that membrane permeability can be achieved by engaging all amide (NH) groups in internal hydrogen bonding interactions. Additionally, designs with exposed NH groups can be made membrane permeable through the design of an alternative isoenergetic fully hydrogen-bonded state favored in the lipid membrane. The ability to design membrane-permeable and orally bioavailable peptides with high structural accuracy has significant implications for the development of next-generation macrocycle therapeutics.
Article
Multidisciplinary Sciences
Arunima Mishra, Irena Cosic, Ivan Loncarevic, Drasko Cosic, Hansel M. Fletcher
Summary: Antimicrobial resistance is a global public health concern that requires new treatments, especially for multidrug-resistant bacteria. This study used the Resonant Recognition Model to evaluate the structure-function properties of beta-lactamase proteins and designed peptides as inhibitors, showing promising results.
Article
Multidisciplinary Sciences
Pirkka-Pekka Laurila, Peiling Luan, Martin Wohlwend, Nadege Zanou, Barbara Crisol, Tanes Imamura de Lima, Ludger J. E. Goeminne, Hector Gallart-Ayala, Minho Shong, Julijana Ivanisevic, Nicolas Place, Johan Auwerx
Summary: Inhibition of sphingolipid synthesis, targeting multiple pathogenic pathways, shows promise as a potential treatment for muscular dystrophies.
Article
Chemistry, Multidisciplinary
Matthew G. Alteen, Hayden Peacock, Richard W. Meek, Jil A. Busmann, Sha Zhu, Gideon J. Davies, Hiroaki Suga, David J. Vocadlo
Summary: This study applied an mRNA display technology with genetic code reprogramming to identify macrocyclic peptides that can inhibit O-GlcNAc transferase (OGT) activity. These macrocycles bind to the tetratricopeptide repeats of OGT and inhibit its activity through an allosteric mechanism. The high potency and novel mechanism of action of these OGT ligands may contribute to further understanding the specificity and regulation of OGT.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Cell Biology
Suhila Sawesi, Sridhar A. Malkaram, Zakaria Y. Abd Elmageed, Tamer E. Fandy
Summary: This study compared the effects of curcumin and dimethoxycurcumin (DMC) on histone posttranslational modifications and enzymatic activity. It was found that both drugs had similar effects on the activity of histone lysine methyltransferase (HKMTs) and histone lysine demethylase (HKDMs) enzymes. However, the changes in histone modifications induced by the two drugs were different. These findings support the use and development of curcumin and DMC as epigenetic modifiers in cancer treatment.
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Albert A. Antolin, Domenico Sanfelice, Alisa Crisp, Eloy Villasclaras Fernandez, Ioan L. Mica, Yi Chen, Ian Collins, Aled Edwards, Susanne Mueller, Bissan Al-Lazikani, Paul Workman
Summary: The Chemical Probes Portal is a public resource for researchers to select and use high-quality chemical probes. Chemical probes are crucial for protein function research and drug discovery, but the use of low-quality probes has led to erroneous conclusions. The portal provides background, principles, content, and technical development, and encourages researcher involvement.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Claudia Tredup, Benardina Ndreshkjana, Natalie S. Schneider, Amelie Tjaden, Aurino M. Kemas, Sonia Youhanna, Volker M. Lauschke, Benedict-Tilman Berger, Andreas Kraemer, Lena M. Berger, Sandra Roehm, Stefan Knapp, Henner F. Farin, Susanne Mueller
Summary: Well-characterized small molecules are crucial for studying target proteins in biology and therapy. However, many compounds lack the necessary potency and selectivity for mechanistic cellular studies. The donated chemical probe (DCP) library provides an openly available collection of valuable and well-characterized tools, including a systematic description and comprehensive characterization data. It represents a unique resource for the biomedical research community.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Mohamed Hasyeoui, Frederic Lassagne, William Erb, Manal Nael, Khaled M. Elokely, Apirat Chaikuad, Stefan Knapp, Adrian Jorda, Soraya L. Vall, Emie Quissac, Maite Verreault, Thomas Robert, Stephane Bach, Ali Samarat, Florence Mongin
Summary: The effects of FL-291 on the viability of neuroblastoma cells were investigated and found to have no significant impact on cell survival. Structural analysis revealed similar binding modes for FL-291 and CD-07 with GSK-3 beta. A library of analogs was designed and synthesized, and the new inhibitor MH-124 exhibited clear selectivity for GSK-3 alpha.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Rohit Arora, Joannes T. M. Linders, Samia Aci-Seche, Thomas Verheyen, Erika Van Heerde, Dirk Brehmer, Apirat Chaikuad, Stefan Knapp, Pascal Bonnet
Summary: The mutation V600E in B-Raf leads to mitogen activated protein kinase (MAPK) pathway activation, uncontrolled cell proliferation, and tumorigenesis. ATP competitive type I B-Raf inhibitors efficiently block the MAPK pathways in B-Raf mutant cells but induce conformational changes in the wild type B-Raf (wtB-Raf) kinase domain causing paradoxical hyperactivation. Type II inhibitors prevent heterodimerization by binding the kinase in the DFG-out conformation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Marcel Rak, Roberta Tesch, Lena M. Berger, Ekaterina Shevchenko, Monika Raab, Amelie Tjaden, Rezart Zhubi, Dimitrios-Ilias Balourdas, Andreas C. Joerger, Antti Poso, Andreas Kra, Lewis Elson, Aleksandar Luc, Thales Kronenberger, Thomas Hanke, Klaus Strebhardt, Mourad Sanhaji, Stefan Knapp
Summary: Salt-inducible kinases 1-3 (SIK1-3) are important regulators of cellular homeostasis. This study presents a structure-based approach to improve the selectivity of inhibitors targeting SIK kinases, resulting in the development of a valuable tool compound, MR22, which showed excellent selectivity and phenotypic effects in ovarian cancer cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Han Wee Ong, Anna Truong, Frank Kwarcinski, Chandi de Silva, Krisha Avalani, Tammy M. Havener, Michael Chirgwin, Kareem A. Galal, Caleb Willis, Andreas Kramer, Shubin Liu, Stefan Knapp, Emily R. Derbyshire, Reena Zutshi, David H. Drewry
Summary: Malaria is a global health problem with high morbidity and mortality rates. The emergence of drug resistance against current treatments emphasizes the need for alternative antimalarials. In this study, we discovered Ki8751 as an inhibitor of essential kinase PfPK6 and identified two compounds (67 and 79) with potent antiplasmodial activity against both blood and liver stages of malaria.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Takayuki Katoh, Hiroaki Suga
Summary: Using a chimeric initiator tRNA and EF-P can effectively suppress the N-terminal drop-off event induced by noncanonical initiator substrates, leading to the synthesis of full-length peptides. By optimizing translation conditions, complete suppression of exotic amino acids and up to a 1000-fold increase in expression level of full-length peptides can be achieved.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Oncology
Leonore Novak, Maria Petrosino, Alessandra Pasquo, Apirat Chaikuad, Roberta Chiaraluce, Stefan Knapp, Valerio Consalvi
Summary: ERK2 is a key player in the Ras-Raf-MEK-ERK signal transduction cascade and its variants in the common docking site have been found in cancer tissues. This study provides a comprehensive analysis of the structural, functional, and stability data of ERK2 wild-type and variants. Understanding the impact of single nucleotide variations on ERK2 can help design alternative therapies and move towards personalized medicine.
Article
Chemistry, Multidisciplinary
H. T. Henry Chan, A. Sofia F. Oliveira, Christopher J. Schofield, Adrian J. Mulholland, Fernanda Duarte
Summary: The SARS-CoV-2 main protease (M-pro) is crucial in the coronavirus lifecycle by breaking down viral polyproteins. This study used dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to examine the behavior of M-pro with and without substrates. The results reveal communication between M-pro subunits and identify networks associated with allosteric inhibition and nirmatrelvir resistance. These findings suggest that certain mutations can lead to drug resistance by altering the allosteric behavior of M-pro. Overall, the study demonstrates the usefulness of D-NEMD in identifying functionally relevant allosteric sites and networks, including those relevant to drug resistance.
News Item
Biochemistry & Molecular Biology
Stefan Knapp, Susanne Mueller
Summary: The quality and appropriate use of chemical tools play a crucial role in determining the quality and reliability of scientific data based on their utilization. Two papers now extend criteria to new modalities and critically review adherence to established guidelines.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
William D. Figg Jr, Giorgia Fiorini, Rasheduzzaman Chowdhury, Yu Nakashima, Anthony Tumber, Michael A. McDonough, Christopher J. Schofield
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2023)
Article
Cell Biology
Chanchal Chauhan, Andreas Kraemer, Stefan Knapp, Mark Windheim, Alexey Kotlyarov, Manoj B. Menon, Matthias Gaestel
Summary: This study investigates the role of MAPK-activated protein kinase 2 (MK2) in cell death and identifies 5-Iodotubercidin (5-ITu) as a potent compound that sensitizes MK2-deficient cells to TNF-induced death. It is found that 5-ITu induces RIPK1-dependent necroptosis by suppressing IKK signaling in the absence of MK2 activity.
CELL DEATH DISCOVERY
(2023)
Article
Chemistry, Multidisciplinary
Mariska de Munnik, Pauline A. A. Lang, Francisco De Dios Anton, Monica Cacho, Robert H. Bates, Jurgen Brem, Beatriz Rodriguez Miquel, Christopher J. Schofield
Summary: Disrupting bacterial cell wall biosynthesis in Mycobacterium tuberculosis is a promising approach for treating tuberculosis. In this study, a high-throughput assay was used to identify potent inhibitors of L,D-transpeptidase Ldt(Mt2), which plays an essential role in the formation of cell wall peptidoglycan. These inhibitors were found to react covalently with the catalytic cysteine of Ldt(Mt2) and showed bactericidal effects on M. tuberculosis.
Article
Biochemistry & Molecular Biology
Anthony Tumber, Eidarus Salah, Lennart Brewitz, Thomas P. Corner, Christopher J. Schofield
Summary: Jumonji-C (JmjC) domain-containing protein 5 (JMJD5) is an oxygenase linked to circadian rhythm and cancer biology. Synthetic 2OG derivatives with cyclic carbon backbones are alternative cosubstrates of JMJD5, demonstrating structural similarity to factor inhibiting hypoxia-inducible transcription factor HIF-a (FIH). Broad-spectrum 2OG oxygenase inhibitors are also efficient JMJD5 inhibitors, while clinical inhibitors like roxadustat do not inhibit JMJD5. Solid phase extraction coupled to mass spectrometry assays will facilitate the development of selective JMJD5 inhibitors for cellular studies.
RSC CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
H. T. Henry Chan, Lennart Brewitz, Petra Lukacik, Claire Strain-Damerell, Martin A. Walsh, Christopher J. Schofield, Fernanda Duarte
Summary: This study investigates how SARS-CoV-2 PLpro binds viral polyprotein-derived oligopeptide substrates through molecular dynamics, docking, and quantum mechanics/molecular mechanics calculations. The results show that a proline located at the P2' position promotes catalysis.
RSC CHEMICAL BIOLOGY
(2023)
