Article
Anesthesiology
Luke Grundy, Cindy Tay, Stewart Christie, Andrea M. M. Harrington, Joel Castro, Fernanda C. C. Cardoso, Richard J. J. Lewis, Vladimir Zagorodnyuk, Stuart M. M. Brierley
Summary: The bladder wall is innervated by a complex network of afferent nerves that detect bladder stretch during filling. Low-voltage-activated T-type calcium channels play a major role in regulating bladder afferent responses to distension.
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
Poanna Tran, Hue N. T. Tran, Kirsten L. McMahon, Jennifer R. Deuis, Lotten Ragnarsson, Alexander Norman, Simon J. Sharpe, Richard J. Payne, Irina Vetter, Christina I. Schroeder
Summary: This study aimed to design new bivalent inhibitors of Na(V)1.7 by combining the pore blocking activity of conotoxins with the gating modifier activity of spider toxins. The potency and selectivity of the resulting bivalent toxins were evaluated by ligating a conotoxin to a spider toxin. The bivalent peptide Pro[LPATG(6)]Sx, resulting from the ligation of ProTx-II and SxIIIC, showed the best combination with conserved potency at hNa(V)1.7.
BIOCONJUGATE CHEMISTRY
(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
Chemistry, Organic
Hue N. T. Tran, Elena Budusan, Natalie J. Saez, Alexander Norman, Isaac J. Tucker, Glenn F. King, Richard J. Payne, Lachlan D. Rash, Irina Vetter, Christina I. Schroeder
Summary: Hi1a is a naturally occurring bivalent spider-venom peptide that shows promise for limiting ischemic damage. However, challenges in synthesizing and producing the peptide in large quantities have hindered progress in this area. Access to synthetic Hi1a is crucial for its development as a pharmacological tool and potential therapeutic.
Article
Pharmacology & Pharmacy
Yashad Dongol, David T. Wilson, Norelle L. Daly, Fernanda C. Cardoso, Richard J. Lewis
Summary: Structure-function and optimization studies of NaV-inhibiting spider toxins have been conducted to develop selective inhibitors for NaV1.7. This study extends the understanding of the structure-function relationships to include other NaV subtypes, NaV1.2 and NaV1.3. Analogues were designed for improved potency and/or subtype-selectivity, with S7R-E18K-rSsp1a and N14D-P27R-rSsp1a identified as promising leads. The findings highlight the challenge of developing subtype-selective spider toxin inhibitors across multiple NaV subtypes.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Edin Muratspahic, Andrew M. White, Cosmin I. Ciotu, Nadine Hochrainer, Natasa Tomasevic, Johannes Koehbach, Richard J. Lewis, Mariana Spetea, Michael J. M. Fischer, David J. Craik, Christian W. Gruber
Summary: In this study, a stable and potent KOR antagonist was developed using cysteine functionalization. The antagonist showed improved selectivity for KOR, and its effectiveness was verified in various cell lines and animal models. This research highlights the value of cysteine stapling in the development of KOR-related drugs.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
