Article
Biochemistry & Molecular Biology
Ritika Gupta, Jyoti Kumari, Soumya Pati, Shailja Singh, Manasi Mishra, Sajal K. Ghosh
Summary: The study investigates the interaction of protein KB1 with different phospholipids at the air-water interface, showing that the electrostatic nature plays a crucial role in determining the initial driving force for protein recognition and attachment to a cellular membrane. The protein induces changes in lipid monolayers, affecting their phase behavior and elastic properties, with the long ranged electrostatic force as the key factor for KB1 to recognize and attach to the membrane before penetrating into the hydrophobic core.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Biochemical Research Methods
Pawel Dabrowski-Tumanski, Pawel Rubach, Wanda Niemyska, Bartosz Ambrozy Gren, Joanna Ida Sulkowska
Summary: Topoly is a Python package designed to detect the topology of (bio)polymers, distinguishing various structures, creating minimal spanning surfaces, and reading different file formats. Its extensive documentation, test cases, and simplicity make it a user-friendly tool for users of all levels of experience.
BRIEFINGS IN BIOINFORMATICS
(2021)
Article
Biochemistry & Molecular Biology
Huawu Yin, Yen-Hua Huang, Sarah A. Best, Kate D. Sutherland, David J. Craik, Conan K. Wang
Summary: In this study, a molecular grafting strategy was used to re-engineer the Nrf2 motif, resulting in the development of MCNr-2c. This optimized peptide showed enhanced stability, cellular uptake, and high affinity for Keap1, leading to increased intracellular expression of two Nrf2 target genes. The integrated approach of encapsulating multiple desired activities into a single molecular entity has broad utility for designing peptide drug leads with therapeutic activity.
ACS CHEMICAL BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Wenyu Liu, Simon J. de Veer, Yen-Hua Huang, Toru Sengoku, Chikako Okada, Kazuhiro Ogata, Christina N. Zdenek, Bryan G. Fry, Joakim E. Swedberg, Toby Passioura, David J. Craik, Hiroaki Suga
Summary: Cyclotides are plant-derived peptides with complex structures that have unique bioactivities and pharmaceutical potential due to their cyclic backbone and cystine knot core. A study using mRNA display identified potent cyclotide-based FXIIa inhibitors, with one inhibitor, cMCoFx1, showing high specificity and potency in inhibiting FXIIa. The interaction between cMCoFx1 and FXIIa at the contact interface suggests that cyclotides are promising cystine knot scaffolds for therapeutic development.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Medicinal
Karina van den Broek, Matthias Epple, Lisa Sophie Kersten, Hubert Kuhn, Achim Zielesny
Summary: The study of cyclotide-induced membrane disruption using dissipative particle dynamics revealed that the interaction between cyclotides and membranes is influenced by factors such as cholesterol content and membrane composition. The hydrophobic patch surface area of cyclotides plays a crucial role in their activity, and substitutions of amino acid residues may lead to super-mutants. Cyclotide mixtures exhibit linearly additive bioactivities without significant sub- or over-additive effects.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Food Science & Technology
Tadashi Kimura
Summary: GTx1-15, an ICK peptide inhibiting various ion channels, exhibits high proteolytic and thermal stability, as well as no cytotoxicity or immunogenicity towards THP-1 cells, making it suitable for peptide drug development and library scaffold applications.
Article
Biochemistry & Molecular Biology
Stefania Mitola, Cosetta Ravelli, Michela Corsini, Alessandra Gianoncelli, Federico Galvagni, Kurt Ballmer-Hofer, Marco Presta, Elisabetta Grillo
Summary: In this study, we propose a multi-step approach for the expression and purification of histidine-tagged recombinant dimeric Gremlin-1 protein, which can act as a BMP antagonist and a VEGFR2 agonist, using HEK293T cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Neha V. Kalmankar, Bhuvaneshwari Rajendrakumar Gehi, Ramanathan Sowdhamini
Summary: Cyclotides extracted from Clitoria ternatea can inhibit the aggregation of beta-amyloid peptides, reduce oxidative stress, and weaken inter-strand hydrogen bonds of A beta peptides, thereby opening up their beta-sheet conformation. This study provides novel structural insights on the interaction between cyclotides and A beta fibrils and describes their potential in anti-amyloid aggregation.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Conan K. Wang, David J. Craik
Summary: This article explores the significance of molecular grafting and its similarities with natural protein functional diversification, highlighting reasons why some scaffolds are more suitable for grafting than others, and suggesting opportunities for improving molecular grafting.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Plant Sciences
Meri Emili F. Pinto, Lai Yue Chan, Johannes Koehbach, Seema Devi, Carsten Grundemann, Christian W. Gruber, Mario Gomes, Vanderlan S. Bolzani, Eduardo Maffud Cilli, David J. Craik
Summary: This study identified and characterized five previously uncharacterized Mobius cyclotides within Palicourea sessilis, demonstrating their potential as immunosuppressants and for the treatment of immune-related disorders. The antiproliferative function of pase cyclotides on human T lymphocytes was found to be dose-dependent, indicating their ability to modulate immune cells. Toxicity on nonimmune cells was also assessed, revealing the pharmacological activities of these novel cyclotides.
JOURNAL OF NATURAL PRODUCTS
(2021)
Article
Medicine, Research & Experimental
Judith Lind, Roland Hellinger, Petra Kudweis, Herwig P. Moll, Jasmin Gattringer, Kathrin Thell, Sophie Edtmayer, Christian W. Gruber, Dagmar Stoiber, Karoline Kollmann
Summary: This study found that cyclotide-based compound T20K and its analogs have an inhibitory effect on the proliferation of anaplastic large cell lymphoma, inducing apoptosis and cell cycle arrest through increased STAT5 and p53 signaling. Mouse experiments showed promising activity of T20K on cancer cells, providing new insights for the treatment of ALCL.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Pharmacology & Pharmacy
Jasmin Gattringer, Olivier Eteme Ndogo, Bernhard Retzl, Carina Ebermann, Christian W. Gruber, Roland Hellinger
Summary: This study identified novel cyclotides from African plants, including alca 1 and alca 2, which showed inhibitory effects on the activity of the human protease POP.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Plant Sciences
Mark A. Jackson, Lai Yue Chan, Maxim D. Harding, David J. Craik, Edward K. Gilding
Summary: Plant molecular farming utilizes plants as bioreactors to produce complex biologics. However, the recombinant expression of therapeutic peptides in plants has been challenging due to their small size and instability. This study demonstrates the successful domestication of Nicotiana benthamiana to produce specific therapeutic peptides through genome edits.
JOURNAL OF EXPERIMENTAL BOTANY
(2022)
Article
Pharmacology & Pharmacy
Erik Melander, Camilla Eriksson, Sara Wellens, Kimia Hosseini, Robert Fredriksson, Fabien Gosselet, Maxime Culot, Ulf Goransson, Margareta Hammarlund-Udenaes, Irena Loryan
Summary: The blood-brain barrier poses challenges to drug delivery to the CNS. CD4, γδT cells, mononuclear phagocytes, mononuclear phagocytes-like antigen-presenting cells, NK cells, NKT cells, resident macrophage-like cells, and neutrophils in the CNS are mainly involved in the innate immune response, while B cells, macrophage-like cells, and T cells play a key role in the acquired immune response.The above findings suggest that cCPPs can serve as potential CNS drug delivery scaffolds, and the differences in their transport across the BBB and cellular uptake abilities are important factors to consider in the development of peptide-based drug delivery systems.
Article
Chemistry, Medicinal
Yasaman Karami, Samuel Murail, Julien Giribaldi, Benjamin Lefranc, Florian Defontaine, Olivier Lesouhaitier, Jerome Leprince, Sjoerd de Vries, Pierre Tuffery
Summary: This article introduces a method for the rational design of head-to-tail cyclization linkers. Firstly, the conformation of cyclized peptides can be accurately predicted based on the linear peptide and linker sequence. Secondly, effective candidate linker sequences can be proposed based on inferred information from protein structures. Finally, case studies demonstrate the potential of this approach for cyclic peptide-based drug design.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Review
Toxicology
Jessica A. I. Muller, Lai Y. Chan, Monica C. Toffoli-Kadri, Marcia R. Mortari, David J. Craik, Johannes Koehbach
Summary: This review highlights the structural diversity of antinociceptive arthropod peptides and emphasizes their vast potential for the discovery of novel analgesic lead molecules.
Article
Chemistry, Medicinal
Xiaopeng Zhu, Shuai Wang, Quentin Kaas, Jinpeng Yu, Yong Wu, Peta J. Harvey, Dongting Zhangsun, David J. Craik, Sulan Luo
Summary: The researchers characterized a novel alpha-conotoxin, LvIC, and its analogues to probe structure-activity relationships at the alpha 6 beta 4 nAChR. They found a potent and specific antagonist, [D1G,delta Q14]LvIC, which could potentially serve as a novel molecular probe to explore alpha 6 beta 4 nAChR-related neurophysiological and pharmacological functions.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Yan Zhou, Peta J. Harvey, Johannes Koehbach, Lai Yue Chan, Alun Jones, Asa Andersson, Irina Vetter, Thomas Durek, David J. Craik
Summary: In this study, a novel method using asparaginyl endopeptidase (AEP)-mediated cyclization was successfully employed to generate backbone cyclic analogues of MVIIA. These cyclic analogues showed improved pharmaceutical properties, including enhanced stability and inhibition of calcium channels. This study highlights the potential of AEP transpeptidases in cyclizing complex peptides and improving the therapeutic value of conotoxins.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biochemical Research Methods
Isabella R. Palombi, Nicole Lawrence, Andrew M. White, Caitlin L. Gare, David J. Craik, Brendan J. McMorran, Lara R. Malins
Summary: Targeted drug delivery with peptide-drug conjugates (PDCs) was investigated as an alternative antimalarial therapy. PDCs with low micromolar potency were developed by conjugating a synthetic peptide derived from an innate human defense molecule with the antimalarial drug primaquine (PQ). Various PDCs were designed to identify the optimal conjugation site and investigate linker length, hydrophilicity, and cleavability. Conjugation within a flexible spacer region of the peptide, with a cleavable linker to liberate the PQ cargo, was crucial for retaining the activity of both the peptide and drug.
BIOCONJUGATE CHEMISTRY
(2023)
Article
Biochemical Research Methods
Qiushi Cao, Cheng Ge, Xuejie Wang, Peta J. Harvey, Zixuan Zhang, Yuan Ma, Xianghong Wang, Xinying Jia, Mehdi Mobli, David J. Craik, Tao Jiang, Jinbo Yang, Zhiqiang Wei, Yan Wang, Shan Chang, Rilei Yu
Summary: With the rise of multidrug-resistant bacteria, antimicrobial peptides (AMPs) have emerged as potential alternatives to traditional antibiotics for treating bacterial infections. However, traditional methods of discovering and designing AMPs are time-consuming and costly. This study utilized deep learning techniques, including sequence generative adversarial nets, bidirectional encoder representations from transformers, and multilayer perceptron, to design and identify AMPs. Six candidate AMPs were then screened and one of them, A-222, showed inhibition against both gram-positive and gram-negative bacteria. Structural analysis and subsequent structure-activity relationship studies led to the design of peptide analogs with increased activity against specific bacteria. Overall, deep learning holds great promise in accelerating the discovery of novel AMPs and could have significant implications in developing new antimicrobial treatments.
BRIEFINGS IN BIOINFORMATICS
(2023)
Review
Biochemistry & Molecular Biology
Xiaorong Liu, Sonia T. Henriques, David J. Craik, Lai Yue Chan
Summary: This article introduces Gomesin, a cationic antimicrobial peptide isolated from the haemocytes of the Brazilian tarantula Acanthoscurria gomesiana and can be chemically produced. Gomesin exhibits a range of biological activities against therapeutically relevant pathogens and has been used for drug design and development. The review provides an overview of the discovery, structure-activity relationships, mechanism of action, biological activity, and potential clinical applications of Gomesin.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Zitong Zhao, Teng Pan, Shen Chen, Peta J. Harvey, Jinghui Zhang, Xiao Li, Mengke Yang, Linhong Huang, Shoushi Wang, David J. Craik, Tao Jiang, Rilei Yu
Summary: mu-Conotoxin KIIIA is a selective blocker of sodium channels with strong inhibitory activity against Nav1.7. Its structural modification and synthesis are challenging due to the presence of three pairs of disulfide bonds. In this study, three KIIIA analogues with one disulfide bond deleted were designed and synthesized. Among them, analogue KIIIA-1 showed the highest inhibitory activity on hNav1.7. A computational model was used to determine its binding pattern to hNav1.7 and guide the design of second and third-generation analogues. Peptide 37, the most potent analogue, exhibited significantly improved inhibitory activity on hNav1.7 and demonstrated potent analgesic effects in an in vivo pain model.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Plant Sciences
Abhishek Bajpai, Mark A. Jackson, Yen-Hua Huang, Kuok Yap, Qingdan Du, Tevin Chui-Ying Chau, David J. Craik, Edward K. Gilding
Summary: Cyclotides are stable and cyclic mini-proteins found in plants, which have nematicidal and anthelmintic activities. Extracts from four major cyclotide-producing plants were tested for their nematicidal properties and were found to be effective against Caenorhabditis elegans. The isolated cyclotides caused damage to the worms' mouth, pharynx, and midgut or membrane, and membrane disruption was implicated in their toxicity and death. The results provide a simple assay design to explore the nematicidal activities of plant extracts and purified cyclotides on C. elegans.
JOURNAL OF NATURAL PRODUCTS
(2023)
Review
Chemistry, Medicinal
Linh T. T. Nguyen, David J. J. Craik, Quentin Kaas
Summary: The venom of marine cone snails contains peptide toxins known as conopeptides, particularly conotoxins that are rich in disulfide bonds. Previous publications have mentioned the significant interest in conopeptides due to their potent and selective activity, but there has not been a formal analysis quantifying the popularity of the field. In this study, we conducted a bibliometric analysis of cone snail toxin literature from 2000 to 2022, which revealed the prolific nature of conopeptide research, with an average of 130 research articles per year.
Article
Biochemistry & Molecular Biology
Marie Morin, Mathias Joesson, Conan K. Wang, David J. Craik, Sandie M. Degnan, Bernard M. Degnan
Summary: This study investigates the impact of captivity on the physiology and health of crown-of-thorns starfish by comparing gene expression in wild and captive individuals. The results show significant differences in gene expression between wild and captive starfish, with genes involved in oxidative stress and energy metabolism upregulated in captivity. This suggests that caution should be taken when extrapolating results from captive marine animals to their wild counterparts.
Review
Biochemistry & Molecular Biology
Tristan J. Tyler, Thomas Durek, David J. Craik
Summary: Bioactive peptides are a diverse group of molecules with varied structures and functions. However, their use as drug candidates has been limited due to inherent shortcomings, including short half-lives and poor cell permeability. This review explores the use of molecular engineering to insert bioactive sequences into constrained scaffolds with desired pharmaceutical properties. Specifically, the focus is on cyclic disulfide-rich scaffolds, either naturally derived or engineered, which are intrinsically stable and amenable to sequence modifications, making them privileged frameworks in drug design.
Article
Biochemical Research Methods
Mark A. A. Jackson, Jing Xie, Linh T. T. Nguyen, Xiaohan Wang, Kuok Yap, Peta J. J. Harvey, Edward K. K. Gilding, David J. J. Craik
Summary: Multiple sclerosis (MS) is a debilitating disease that requires prolonged treatment. The experimental therapeutic [T20K]kB1, a mutant of a plant peptide, shows promise for oral dosing and stability due to its cyclic structure. This study demonstrates the production of [T20K]kB1 in the Nicotiana benthamiana plant, providing a sustainable and cost-effective production method for cyclotide-based therapeutics.
TRANSGENIC RESEARCH
(2023)
Article
Immunology
Zhian Chen, Yanfang Cui, Yin Yao, Bo Liu, Joseph Yunis, Xin Gao, Naiqi Wang, Pablo F. Canete, Zewen Kelvin Tuong, Hongjian Sun, Hao Wang, Siling Yang, Runli Wang, Yew Ann Leong, David Simon Davis, Jiahuan Qin, Kaili Liang, Jun Deng, Conan K. Wang, Yen-Hua Huang, Jonathan A. Roco, Sam Nettelfield, Huaming Zhu, Huajun Xu, Zhijia Yu, David Craik, Zheng Liu, Hai Qi, Christopher Parish, Di Yu
Summary: In antibody responses, mutated germinal center B (BGc) cells are positively selected for reentry or differentiation, with the support of TFH cell-derived signals including CD40 and IL-21. The binding and signaling of IL-21 in BGc cells is reduced compared to non-BGc cells, due to low cellular heparan sulfate (HS) sulfation. Ndst1-mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength, and selective desensitization to IL-21 occurs in BGc cells. Therefore, the biochemical regulation of IL-21 availability and signal strength plays a crucial role in GC selection.
SCIENCE IMMUNOLOGY
(2023)
Article
Chemistry, Medicinal
Edin Muratspahic, Despoina Aslanoglou, Andrew M. White, Claudia Draxler, Xaver Kozisek, Zara Farooq, David J. Craik, Peter J. McCormick, Thomas Durek, Christian W. Gruber
Summary: In this study, peptide ligands for MC4R were designed using a peptide drug design approach. The designed peptides fully activated MC4R and recruited beta-arrestin-2 with higher efficacies and potencies than the endogenous alpha-MSH. These findings suggest the potential of these novel peptide ligands in developing safer and more effective antiobesity drugs.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Microbiology
Nicole L. van der Weerden, Kathy Parisi, James A. Mckenna, Brigitte M. Hayes, Peta J. Harvey, Pedro Quimbar, Sean R. Wevrett, Prem K. Veneer, Owen Mccorkelle, Shaily Vasa, Rosemary Guarino, Simon Poon, Yolanda M. Gaspar, Michael J. Baker, David J. Craik, Rob B. Turner, Marc B. Brown, Mark R. Bleackley, Marilyn A. Anderson
Summary: Onychomycosis, or fungal nail infection, can cause pain, discomfort, and psychological and social consequences. Current treatments are limited by poor nail penetration or potential toxicity. Plant defensins, such as Ppdef1, have stable structures and potent antifungal activity, making them promising treatments. Ppdef1 shows excellent activity against a range of fungal pathogens, including Trichophyton rubrum, the major cause of onychomycosis.