Review
Pharmacology & Pharmacy
Talhat Chaudhry, Christopher R. Coxon, Kehinde Ross
Summary: This review highlights the advances made in small molecule and peptide inhibitors of miRNA processing, with an emphasis on peptide features that regulate miRNA expression.
DRUG DISCOVERY TODAY
(2022)
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)
Review
Chemistry, Multidisciplinary
Raffaella Bucci, Evangelos Georgilis, Alexander M. Bittner, Maria L. Gelmi, Francesca Clerici
Summary: Electrospinning is a versatile technique widely used for fiber preparation, where high molecular weight isn't essential. Peptides containing natural and non-natural amino acids are gaining interest in electrospinning, with potential advantages but still in early stages of research. Characterization techniques specific to peptide fibers are being developed.
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
Biochemistry & Molecular Biology
Sunit Pal, Peter 't Hart
Summary: The use of cyclic peptides to target RNA provides potential therapeutic options, and lessons learned from past examples can guide the development of novel potent and selective ligands.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Pharmacology & Pharmacy
Ian M. Henderson, Carlissa Marez, Karol Dokladny, Jane Smoake, Maria Martinez, David Johnson, George R. Uhl
Summary: The receptor type protein tyrosine phosphatase D (PTPRD) is expressed by neurons and related to various phenotypes. By identifying candidate brain substrates for PTPRD and discovering the positive allosteric modulation effect of flavonols, this study provides insights into the potential therapeutic targets for reducing Alzheimer's disease.
BIOCHEMICAL PHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Vladislav Deigin, Natalia Linkova, Olga Volpina
Summary: This article presents a chemical platform based on branched piperazine-2,5-diones for creating orally available biologically active peptidomimetics. The platform includes a bio-carrier with built-in functionally active peptide fragments or bioactive molecules that are covalently attached via linkers. The developed platform allows for the transformation of small peptides into orally stable compounds displaying the same activity. Various peptidomimetics with hemostimulating, hemosuppressing, and adjuvant activity were prepared using this approach, and new examples of enantiomeric molecules demonstrating reciprocal biological activity are also presented. The article concludes by summarizing the evolutionary approach of short peptide pharmaceutical development.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Srinivasaraghavan Kannan, Pietro G. A. Aronica, Thanh Binh Nguyen, Jianguo Li, Chandra S. Verma
Summary: S100B (beta beta) proteins are a family of multifunctional proteins that play important roles in disease treatment. Designed stapled peptides, used as S100B (beta beta) binders through structural analysis and simulation, serve as diagnostic tools and novel therapeutic approaches.
Article
Multidisciplinary Sciences
Ram Kandasamy, Todd M. Hillhouse, Kathryn E. Livingston, Kelsey E. Kochan, Claire Meurice, Shainnel O. Eans, Ming-Hua Li, Andrew D. White, Bernard P. Roques, Jay P. McLaughlin, Susan L. Ingram, Neil T. Burford, Andrew Alt, John R. Traynor
Summary: Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been suggested as potentially safer analgesics compared to traditional opioid drugs, enhancing the activity of endogenous opioid peptides while reducing side effects. Experimental evidence shows that a specific mu-PAM, BMS-986122, can enhance the potency of endogenous opioid peptides and produce antinociceptive effects in mouse models of acute and inflammatory pain. This innovative approach to pain management may offer a safer alternative to conventional opioid medications.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
James Adams, Benjamin P. Thornton, Lydia Tabernero
Summary: The study identified unique ligand cluster distributions specific to kinase interaction motif protein tyrosine phosphatases (KIM-PTPs) and found that ligand clusters coincide with functional and substrate binding sites in these PTPs. Ligand efficiency index (LEI) analysis showed that binders in these clusters reside in a more drug-like chemical-biological space. Differences in clusters across all KIM-PTPs highlight a distinct and specific profile for each phosphatase, with potential for exploiting unexplored allosteric functional sites for drug development.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Chemistry, Medicinal
Ning Wang, Shilin Zhu, Dan Lv, Yajun Wang, Muhammad B. Khawar, Haibo Sun
Summary: Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) is a crucial regulator in the cell cycle and its activating mutations are significant in various cancer developments, making it an essential target for antitumor drugs. However, due to the highly conserved amino acid sequence and positively charged active site of SHP2, finding inhibitors with high affinity and sufficient cell permeability is challenging, thus rendering SHP2 an undruggable target. Nevertheless, the discovery of allosteric regulation mechanisms presents new prospects for transforming undruggable targets into druggable targets. This review highlights the oncogenic mechanism of SHP2 and summarizes the discovery methods of SHP2 allosteric inhibitors, providing novel strategies for designing and improving SHP2 allosteric inhibitors.
DRUG DEVELOPMENT RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Aaron P. Decker, Abraham F. Mechesso, Guangshun Wang
Summary: Unlike the alpha-helical and beta-sheet antimicrobial peptides (AMPs), amino acid-rich AMPs have limited knowledge. This article conducted a systematic study on rich AMPs (>25%) from different life kingdoms using the Antimicrobial Peptide Database (APD) and program R. Of the 3425 peptides analyzed, 724 rich AMPs were identified. The distribution of rich AMPs differs among animals, bacteria, and plants. Certain amino acids are frequently observed in rich AMPs, while others are occasionally observed or not yet found. These findings can guide peptide design and rich AMPs show promise as future antibiotics.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Guangshun Wang, C. Michael Zietz, Ashok Mudgapalli, Shuona Wang, Zhe Wang
Summary: The antimicrobial peptide database (APD) has been serving the field of antimicrobial peptides for 18 years, documenting database milestones and key events that have shaped its current form. This article compares peptide statistics from 2010 to 2020 and introduces new additions to the database. The APD also includes antimicrobial peptides from host microbiota, which play a crucial role in shaping immune systems and may be linked to various human diseases.
Review
Chemistry, Organic
Aizhan Abdildinova, Mark J. Kurth, Young-Dae Gong
Summary: Peptidomimetics are compounds with promising pharmacological properties that overcome limitations of peptides through backbone modifications. Accessible synthetic methodologies play a key role in peptidomimetic progress, with solid-phase organic synthesis serving as a powerful tool for their preparation. Numerous strategies for peptide backbone modifications via solid-phase synthesis have been developed in the last two decades.
ASIAN JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Shulamit Fluss Ben-Uliel, Faten Habrat Zoabi, Moriya Slavin, Hadas Sibony-Benyamini, Nir Kalisman, Nir Qvit
Summary: Mitochondria are crucial for maintaining cellular energy metabolism and function, while Pink1 is a kinase that regulates mitochondrial function. In this study, a peptide targeting Pink1 was rationally designed and molecular probes with drug-like properties were developed to investigate Pink1's structure and function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Francesca Salvi, Bernhard Hoermann, Javier del Pino Garcia, Miriam Fontanillo, Rita Derua, Monique Beullens, Mathieu Bollen, Orsolya Barabas, Maja Koehn
Summary: PP1 phosphoprotein phosphatase plays a key role in cellular signaling pathways, and aberrant activity is associated with various diseases. Research suggests that inhibitory function of PP1 through phosphorylation of a Thr residue may be mediated by protein complex formation rather than structural changes or substrate competition.
Article
Immunology
Amalia Papadaki, Olympia Tziouvara, Anastasia Kotopouli, Petrina Koumarianou, Anargyros Doukas, Pablo Rios, Isabelle Tardieux, Maja Kohn, Haralabia Boleti
Summary: Leishmania parasites go through distinct developmental transitions including metacyclogenesis and differentiation of metacyclic promastigotes to amastigotes. Phosphoinositide signaling and metabolism play crucial roles in these processes. The LDBPK_220120.1 gene in L. donovani encodes a phosphatase that may be involved in regulatory processes during developmental transitions inside host macrophages.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
H. Ceren Ates, Hasti Mohsenin, Christin Wenzel, Regina T. Glatz, Hanna J. Wagner, Richard Bruch, Nico Hoefflin, Sashko Spassov, Lea Streicher, Sara Lozano-Zahonero, Bernd Flamm, Rainer Trittler, Martin J. Hug, Maja Koehn, Johannes Schmidt, Stefan Schumann, Gerald A. Urban, Wilfried Weber, Can Dincer
Summary: Personalized antibiotherapy can maximize efficacy, minimize side effects, and prevent drug resistance. To better integrate therapeutic drug monitoring into clinical practice, a versatile biosensor with an antibody-free assay for on-site testing is introduced. This system offers rapid, low-cost, sample-independent, and multiplexed analysis, which can potentially shift the paradigm of one-size-fits-all strategy.
ADVANCED MATERIALS
(2022)
Review
Biochemistry & Molecular Biology
Bernhard Hoermann, Maja Koehn
Summary: Phosphorylation of serine and threonine plays a crucial role in cell signaling, with the timely attachment, binding, and removal of phosphate being key factors in fast modulation of regulatory sites. The selection of phosphorylation sites is largely influenced by the sequence motif and the presence of regulatory proteins, while the context of substrate structure also affects recognition mechanisms. The interplay between kinases, pSer/pThr-binding proteins, and phosphatases at these crossroads of signaling motifs is essential for cellular adaptation to signals.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2021)
Review
Biochemistry & Molecular Biology
Jorg Hoehfeld, Thomas Benzing, Wilhelm Bloch, Dieter O. Fuerst, Sebastian Gehlert, Michael Hesse, Bernd Hoffmann, Thorsten Hoppe, Pitter F. Huesgen, Maja Koehn, Waldemar Kolanus, Rudolf Merkel, Carien M. Niessen, Wojciech Pokrzywa, Markus M. Rinschen, Dagmar Wachten, Bettina Warscheid
Summary: Mechanical stress can threaten protein structure and proteome integrity, but cells have folding and degradation systems to combat this stress. These systems play crucial roles in cell differentiation, adhesion, and migration, and are essential for maintaining the integrity of various tissues.
Article
Genetics & Heredity
Teresa Rubio, Judith Weyershaeuser, Marta G. Montero, Andreas Hoffmann, Pablo Lujan, Martin Jechlinger, Rocio Sotillo, Maja Koehn
Summary: Overexpression of the phosphatase PRL-3 leads to the death of intestinal stem cells and expansion of Paneth cells, while elevated PRL-3 phosphatase activity in healthy intestinal epithelium impairs intestinal cell homeostasis, increasing susceptibility to tumor formation.
JOURNAL OF MOLECULAR MEDICINE-JMM
(2021)
Article
Cell Biology
Meenal Chaudhari, Niraj Thapa, Hamid Ismail, Sandhya Chopade, Doina Caragea, Maja Koehn, Robert H. Newman, Dukka B. KC
Summary: Phosphorylation and dephosphorylation play crucial roles in cellular processes such as metabolism, migration, and division. While prediction methods for phosphorylation sites are well-developed, research on dephosphorylation sites is limited. Researchers have employed a deep learning model to develop a tool for predicting potential dephosphorylation sites, achieving efficient outcomes for both phosphoserine/phosphothreonine and phosphotyrosine residues.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Biology
Jennifer J. Schwarz, Lorenz Grundmann, Thomas Kokot, Kathrin Klasener, Sandra Fotteler, David Medgyesi, Maja Kohn, Michael Reth, Bettina Warscheid
Summary: This study identified and quantified human B cell signaling components using the B cell line Ramos, showing that PTP1B negatively modulates BCR signaling by dephosphorylating specific phosphotyrosines in B cell-specific receptor proteins and downstream signaling components. The study also revealed several potential substrates and binding partners of PTP1B, providing new insights into the regulation of B cell activation.
LIFE SCIENCE ALLIANCE
(2021)
Article
Biotechnology & Applied Microbiology
Helena Engel, Felix Guischard, Fabian Krause, Janina Nandy, Paulina Kaas, Nico Hoefflin, Maja Koehn, Normann Kilb, Karsten Voigt, Steffen Wolf, Tahira Aslan, Fabian Baezner, Salome Hahne, Carolin Ruckes, Joshua Weygant, Alisa Zinina, Emir Bora Akmeric, Enoch B. Antwi, Dennis Dombrovskij, Philipp Franke, Klara L. Lesch, Niklas Vesper, Daniel Weis, Nicole Gensch, Barbara Di Ventura, Mehmet Ali Oeztuerk
Summary: The use of D-peptides, composed of dextrorotatory enantiomers, offers improved stability and efficacy in peptide therapeutics. The web server finDr allows for the computational identification and optimization of D-peptide ligands to any protein structure, providing a tool for predicting optimal binders. This approach facilitates D-peptide discovery in biotechnology and biomedicine, presenting a cost-effective and user-friendly alternative to conventional methods.
SYNTHETIC AND SYSTEMS BIOTECHNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Miriam Fontanillo, Malgorzata Trebacz, Christopher D. Reinkemeier, Daniela Aviles Huerta, Ulrike Uhrig, Peter Sehr, Maja Kohn
Summary: This study presents the sequence optimization of a 23mer PDP to a 5mer peptide, providing a lead structure for targeting PP1 in therapy or for its use in phosphatase-recruiting chimeras in the future.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Review
Cell Biology
Thomas Kokot, Maja Koehn
Summary: Protein phosphorylation is a common post-translational modification that regulates protein function. Phosphoprotein phosphatases (PPPs) play a significant role in cellular functions by dephosphorylating phosphorylated residues. Recent advancements in (phospho-)proteomics, structural biology, and computational biology have provided new insights into the complex mechanism of PPP holoenzyme regulation and substrate selectivity.
JOURNAL OF CELL SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Jeremy E. Chojnacki, Laura Scheinost, Yansong Wang, Maja Koehn
Summary: Protein phosphatase-1 (PP1) is an enzyme involved in various cellular processes. PP1-disrupting peptides (PDPs) selectively bind to PP1 and release its activity. To target PDPs to specific cellular compartments, PDP-Mem was developed, which activates PP1 alpha in vitro and localizes to the cell membrane. However, in cells, PDP-Mem activates the MAPK signaling pathway and induces calcium release independently of PP1 activation, due to the combination of cell-penetrating polybasic sequence and membrane-targeting palmitoylated lysine.
JOURNAL OF PEPTIDE SCIENCE
(2023)
Editorial Material
Chemistry, Multidisciplinary
Eva-Maria Duerr, Maja Koehn
ACS CENTRAL SCIENCE
(2022)
Article
Multidisciplinary Sciences
Karolina Pavic, Nikhil Gupta, Judit Domenech Omella, Rita Derua, Anna Aakula, Riikka Huhtaniemi, Juha A. Maatta, Nico Hofflin, Juha Okkeri, Zhizhi Wang, Otto Kauko, Roosa Varjus, Henrik Honkanen, Daniel Abankwa, Maja Kohn, Vesa P. Hytonen, Wenqing Xu, Jakob Nilsson, Rebecca Page, Veerle Janssens, Alexander Leitner, Jukka Westermarck
Summary: This study reveals the molecular level details and structural mechanisms of PP2A-B56 alpha inhibition by the oncoprotein CIP2A. CIP2A displaces the PP2A-A subunit and forms a pseudotrimer, blocking the B56 alpha substrate binding site and stabilizing CIP2A protein.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Kevin Ritter, Nikolaus Jork, Anne-Sophie Unmuessig, Maja Koehn, Henning J. J. Jessen
Summary: Inositol phosphates, a family of highly charged messenger molecules, have diverse functions in cellular processes. The phosphorylation patterns result in a vast array of compounds. This study presents a method using NMR measurements for enantiomer assignment, enabling the differentiation of enantiomers. The method was applied to various inositol phosphates and will aid in the assignment of biologically relevant isomers.