Review
Pharmacology & Pharmacy
Marina Buyanova, Dehua Pei
Summary: Intracellular protein-protein interactions are challenging targets for traditional drug modalities. Macrocyclic peptides have proven to be effective inhibitors, but they are generally impermeable to the cell membrane. Recent advances in MP science and technology have allowed for the development of cell-permeable MPs that can modulate intracellular PPI targets.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2022)
Review
Pharmacology & Pharmacy
Maria C. Lucana, Yolanda Arruga, Emilia Petrachi, Albert Roig, Roberta Lucchi, Benjami Oller-Salvia
Summary: This review explores the application of protease-resistant targeting peptides and cell-penetrating peptides, highlighting the use of enantio/retro-enantio isomerization and cyclization to enhance peptide efficiency and transport capacity. While conjugation provides some protection against proteolysis, modifying peptide sequences for increased protease resistance significantly improves homing and transport efficiency.
Article
Multidisciplinary Sciences
Shannon L. Speer, Wenwen Zheng, Xin Jiang, I-Te Chu, Alex J. Guseman, Maili Liu, Gary J. Pielak, Conggang Li
Summary: Protein-protein interactions are more influenced by chemical interactions than hard-core repulsions in cells; increasing negative charge on the homodimer surface enhances stability in cells; oocytes are less crowded than E. coli cells, leading to greater stability of protein complexes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Binu Jacob, Alicia Vogelaar, Enrique Cadenas, Julio A. Camarero
Summary: This review provides an overview of the properties of cyclotides and their potential for developing novel peptide-based therapeutics. Cyclotides, with their cell-permeability properties, have shown great promise for targeting biomolecular interactions. Molecular techniques employing the cyclotide scaffold have been highly effective for selecting bioactive cyclotides.
Article
Chemistry, Medicinal
Rikeshwer Prasad Dewangan, Devesh Pratap Verma, Neeraj Kumar Verma, Ankit Gupta, Garima Pant, Kalyan Mitra, Saman Habib, Jimut Kanti Ghosh
Summary: In this study, a new type of proline-rich peptide mimetic was designed and synthesized. These lipopeptides exhibited significant antimicrobial activity against resistant bacteria and demonstrated resistance against trypsin digestion. They also showed synergistic antimicrobial activity when combined with tested antibiotics. The lipopeptides were found to interact with the bacterial ribosome and inhibit protein synthesis. Furthermore, they demonstrated superior clearance of bacteria compared to a conventional antibiotic.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Agriculture, Multidisciplinary
Carmen Lammi, Giovanna Boschin, Martina Bartolomei, Anna Arnoldi, Gianni Galaverna, Luca Dellafiora
Summary: This study combined computational and in vitro investigations to precisely describe the chemical basis of potent inhibitory peptides. A novel and potent ACE inhibitory peptide was discovered, and the findings could serve as a blueprint for designing new inhibitory peptides.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Netha Ulahannan, Ronald Cutler, Reanna Dona-Termine, Claudia A. Simoes-Pires, N. Ari Wijetunga, Matthew McKnight Croken, Andrew D. Johnston, Yu Kong, Shahina B. Maqbool, Masako Suzuki, John M. Greally
Summary: By studying the gene expression and chromatin states of human fibroblasts infected with Toxoplasma gondii, we gained insights into the molecular interactions between the intracellular pathogen and its host cell. We found that host cell genes were activated to regulate cellular processes, some of which were protective of the host cell while others were advantageous to the pathogen. Analysis of the host and parasite genomic information allowed us to annotate the T. gondii genome more accurately and discover new genes and cis-regulatory elements. By inferring the involved transcription factors and cell signaling responses in the host cell, we could understand how T. gondii perturbs host cell physiology.
Article
Chemistry, Multidisciplinary
Jing Wang, Liangbo Hu, Hongyue Zhang, Yu Fang, Tingliang Wang, Huaimin Wang
Summary: Biomolecular condensates play a crucial role in controlling cellular functions, but constructing artificial biomolecular condensates remains challenging. This study presents a general approach to construct biomolecular condensates in lysosomes of living cells for cancer therapy, with potential applications in addressing multiple drug resistance.
ADVANCED MATERIALS
(2022)
Article
Multidisciplinary Sciences
Erwin Pannecoucke, Maaike Van Trimpont, Johan Desmet, Tim Pieters, Lindy Reunes, Lisa Demoen, Marnik Vuylsteke, Stefan Loverix, Karen Vandenbroucke, Philippe Alard, Paula Henderikx, Sabrina Deroo, Franky Baatz, Eric Lorent, Sophie Thiolloy, Klaartje Somers, Yvonne McGrath, Pieter Van Vlierberghe, Ignace Lasters, Savvas N. Savvides
Summary: This study demonstrates the engineering of the Alphabody scaffold into a cell-penetrating protein antagonist against intracellular cancer target MCL-1, with the addition of an albumin-binding moiety to extend serum half-life. The engineered Alphabody reduced tumor burden in mouse tumor xenografts based on myeloma cell lines, providing a proof of concept for using Alphabodies against intracellular disease mediators.
Article
Medicine, Research & Experimental
Rachel M. Lieser, Qirun Li, Wilfred Chen, Millicent O. Sullivan
Summary: Intracellular delivery of protein therapeutics is a challenge, but a fusion modification approach using endosomolytic peptides has shown enhanced endosomal disruption and improved targeting specificity. However, the choice of endosomal escape moiety can affect the cytotoxicity and bioactivity of the delivered protein.
MOLECULAR PHARMACEUTICS
(2022)
Article
Chemistry, Multidisciplinary
Filip Hasecke, Chamani Niyangoda, Gustavo Borjas, Jianjun Pan, Garrett Matthews, Martin Muschol, Wolfgang Hoyer
Summary: The study found that in the assembly of A beta and lysozyme, protofibrils bind to the lateral surfaces of amyloid fibrils, inhibiting the self-proliferation of amyloid fibrils. This suggests that metastable oligomers counteract the replacement by amyloid fibrils through competing for monomers and blocking secondary nucleation sites.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Cell Biology
Carolina A. Parada, Ivan Pires de Oliveira, Mayara C. F. Gewehr, Joao Agostinho Machado-Neto, Keli Lima, Rosangela A. S. Eichler, Lucia R. Lopes, Luiz R. G. Bechara, Julio C. B. Ferreira, William T. Festuccia, Luciano Censoni, Ivarne Luis S. Tersariol, Emer S. Ferro
Summary: This study investigates the intracellular effects of intracellular peptides on protein-protein interactions. The results show that VFD7 and VFD6 peptides can inhibit the rapamycin-induced interaction between FKBP and FRB. Molecular dynamics simulations suggest that VFD7 and VFD6 can bind to FKBP and induce structural changes, providing insights into their mechanism of PPI inhibition. Additionally, intracellular peptides are found to be mainly associated with macromolecular components. Overall, this study provides further evidence for the importance of intracellular peptides in the targeted design of therapeutic molecules for intracellular PPI.
Review
Biochemistry & Molecular Biology
Caroline Donaghy, Jose Gabriel Javellana, Young-Jin Hong, Karrera Djoko, Alfredo M. Angeles-Boza
Summary: Antimicrobial peptides (AMPs) are being studied as an alternative to antibiotics due to their broad-spectrum antimicrobial activity and ability to avoid resistance development. In this review, the focus is on metalloAMPs that interact with the essential metal ion zinc(II) to enhance their antimicrobial efficacy. By understanding the synergistic interactions between AMPs and zinc(II), researchers can develop new antimicrobial agents and accelerate their therapeutic use.
Review
Biochemistry & Molecular Biology
Hao Lin, Srinivasulu Cherukupalli, Da Feng, Shenghua Gao, Dongwei Kang, Peng Zhan, Xinyong Liu
Summary: This article provides concise information on potential entry inhibitors targeting the virus-ACE2 or virus-TMPRSS2 interactions in SARS-CoV-2, which can effectively prevent virus infection.
CURRENT MEDICINAL CHEMISTRY
(2022)
Review
Biotechnology & Applied Microbiology
Ilaria Porello, Francesco Cellesi
Summary: Achieving effective delivery of therapeutic proteins to intracellular targets is crucial for advancing human health. Current methods, such as chemical modification and nanocarrier-based approaches, have limitations in efficiency and safety. Developing more versatile delivery tools that trigger endocytosis or directly deliver proteins to the cytosol is essential for successful therapeutic effects. This article provides an overview of current methods for intracellular protein delivery, highlighting challenges and opportunities for future research.
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
(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
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
Multidisciplinary Sciences
Jan Philipp Menzel, Reuben S. E. Young, Aurelie H. Benfield, Julia S. Scott, Puttandon Wongsomboon, Lukas Cudlman, Josef Cvacka, Lisa M. Butler, Sonia T. Henriques, Berwyck L. J. Poad, Stephen J. Blanksby
Summary: This study introduces a workflow for discovering new fatty acids, which adds more than 100 fatty acids to the human lipidome. The traditional methods often fail to detect the isomers of unsaturated fatty acids. By coupling liquid chromatography and mass spectrometry with gas-phase ozonolysis of double bonds, this workflow enables the rapid identification of fatty acids in complex media and even in instances of incomplete chromatographic separation. The application of this method can reveal changes in lipid metabolism.
NATURE COMMUNICATIONS
(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.
Review
Pharmacology & Pharmacy
Karlie R. Sharma, Christine M. Colvis, Griffih P. Rodgers, Douglas M. Sheeley
Summary: There are many genes within the druggable genome that have not been studied, and the US National Institutes of Health's program provides resources to explore these genes, with the potential for rapid impact on human health.
DRUG DISCOVERY TODAY
(2024)
Review
Pharmacology & Pharmacy
Mohammad Sameer Khan, B. H. Jaswanth Gowda, Waleed H. Almalki, Tanuja Singh, Amirhossein Sahebkar, Prashant Kesharwani
Summary: Mitochondria-specific functional liposomes hold great potential for cancer therapy. This review discusses the association between mitochondria and tumor formation, as well as the advantages of liposomes in delivering drugs to mitochondria.
DRUG DISCOVERY TODAY
(2024)
Review
Pharmacology & Pharmacy
Choong Yong Ung, Cristina Correia, Hu Li, Christopher M. Adams, Jennifer J. Westendorf, Shizhen Zhu
Summary: With increasing human life expectancy, the global medical burden of chronic diseases is growing. Chronic diseases often involve malfunctioning of multiple organs, and understanding the interorgan crosstalk is crucial to understanding the etiology of chronic diseases. Researchers have proposed the locked-state model (LoSM) and cutting-edge systems biology and artificial intelligence strategies to decipher chronic multiorgan locked states. The findings have important clinical implications for improving treatments for chronic diseases.
DRUG DISCOVERY TODAY
(2024)
