Article
Chemistry, Medicinal
Ryuichiro Ishitani, Toshiki Kataoka, Kentaro Rikimaru
Summary: The automatic design of molecules with specific chemical and biochemical properties is crucial in material informatics and computational drug discovery. This study introduces a novel representation of molecules, called Reversible Junction Tree (RJT), which can be converted back to the original molecule without external information. By utilizing deep reinforcement learning, the molecular design and optimization problem is formulated as a tree-structure construction, enabling efficient optimization in simple benchmark tasks. The applicability of the method is further demonstrated in multiobjective optimization and fine-tuning of reinforcement learning models in drug discovery.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Valentina Albanese, Sonia Missiroli, Mariasole Perrone, Martina Fabbri, Caterina Boncompagni, Salvatore Pacifico, Tiziano De Ventura, Antonella Ciancetta, Giulio Dondio, Franz Kricek, Paolo Pinton, Remo Guerrini, Delia Preti, Carlotta Giorgi
Summary: A series of aryl sulfonamide derivatives (ASDs) were designed and synthesized to inhibit the activation of the NLRP3 inflammasome. Compounds 6c, 7n, and 10 specifically inhibited NLRP3 activation at nanomolar concentrations without affecting the activation of other inflammasomes. These compounds were also found to reduce IL-1 beta production in vivo and attenuate melanoma tumor growth. The findings suggest that these potent NLRP3 inflammasome inhibitors could be considered for future therapeutic approaches in NLRP3 inflammasome-driven cancer.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Joseph Loscalzo
Summary: Conventional drug discovery relies on identifying protein targets and compounds that alter their function, but recent data suggest its limited success due to the complexity of disease mechanisms. Network medicine, using protein-protein interaction networks, offers a new approach by identifying disease-specific subnetworks and studying the effects of drugs. This unbiased method holds promise for advancing disease understanding and precision therapeutics.
Review
Biochemistry & Molecular Biology
Felix Gayraud, Merlin Klussmann, Ines Neundorf
Summary: This review focuses on recent developments in conjugation techniques for synthesizing cell-penetrating peptide (CPP)-drug conjugates targeting cancer cells, including small organic molecules and metal complexes as cytostatic payloads. The use of bifunctional linkers is gaining attention due to its advantages in linker chemistry, with three main categories of linkers highlighted. Pros and cons of each technique are thoroughly discussed to aid in choosing the optimal conjugation technique for synthesizing a specific CPP-drug conjugate.
Review
Pharmacology & Pharmacy
Amit Kumar Tripathi, Jamboor K. Vishwanatha
Summary: The use of peptide-based drugs for cancer treatment is becoming more significant in the pharmaceutical industry. Anticancer peptides with immunomodulatory activity could be key lead molecules in designing effective cancer therapeutics.
Article
Infectious Diseases
Mengjun Zheng, Ruina Wang, Si Chen, Yan Zou, Lan Yan, Linjing Zhao, Xiang Li
Summary: Stapled analogues of Aurein1.2 peptides showed higher proteolytic stability and helicity compared to the linear counterpart, exhibiting better inhibitory effects on common pathogenic fungi. These stapled peptides may serve as leading compounds for further optimization and antifungal therapy.
Review
Ophthalmology
Ari Stoner, Alon Harris, Francesco Oddone, Aditya Belamkar, Alice Chandra Verticchio Vercellin, Joshua Shin, Ingrida Januleviciene, Brent Siesky
Summary: Carbonic anhydrase inhibitors have been used in the treatment of glaucoma for many years, but are no longer the primary treatment method due to common side effects. Topical CAIs are still used in combination therapies and have been shown to have an impact on glaucoma management.
BRITISH JOURNAL OF OPHTHALMOLOGY
(2022)
Review
Ophthalmology
Chee Wai Wong, Josbert M. Metselaar, Gert Storm, Tina T. Wong
Summary: Ocular anterior segment inflammation is a medical issue that can lead to serious conditions if inadequately treated, with topical steroid eye-drops being the mainstay of treatment. However, drawbacks such as low bioavailability and poor patient compliance necessitate the development of alternative drug delivery systems to improve efficacy. Successes in clinical trials have shown that DDS like Dextenza and INVELTYS may replace traditional eye-drops for managing anterior segment inflammation.
BRITISH JOURNAL OF OPHTHALMOLOGY
(2021)
Article
Ophthalmology
Blake Hugo Fortes, Harris Liou, Lauren A. Dalvin
Summary: Among 996 patients receiving immune checkpoint inhibitors, 28 (2.8%) experienced ophthalmic side effects requiring the attention of an eye care provider. PD-L1-targeted therapy was more likely to cause ocular surface adverse effects, but most ophthalmic events can be managed with targeted therapy without discontinuing life-prolonging immunotherapy.
BRITISH JOURNAL OF OPHTHALMOLOGY
(2021)
Article
Multidisciplinary Sciences
Arun Ramanathan, Jensen Kaplan, Dumitru-Claudiu Sergentu, Jacob A. Branson, Mykhaylo Ozerov, Alexander I. Kolesnikov, Stefan G. Minasian, Jochen Autschbach, John W. Freeland, Zhigang Jiang, Martin Mourigal, Henry S. La Pierre
Summary: This study reveals the failure of the traditional ionic model in tetravalent praseodymium ions, as well as the unusual participation of 4f orbitals in bonding and the anomalous hybridization of the 4f(1) configuration with ligand valence electrons. The competition between crystal-field and spin-orbit-coupling interactions alters the spin-orbital magnetism of tetravalent praseodymium, making it resemble that of high-valent actinides.
NATURE COMMUNICATIONS
(2023)
Article
Plant Sciences
Lindiwe Sibeko, Timothy Johns, Bi-sek Hsiao
Summary: This article aims to collect reported medicinal plant use during pregnancy and postpartum, analyze the most important taxa in relation to key functional purposes, and test the hypothesis that perinatal plant use is non-random. Data from 410 publications showed that 53% of reports were published from 2005 to 2020, indicating a continuous increase in overall data availability. The most frequently reported categories of plant use were uterotonic, prenatal, lactation and post-partum recovery, and newborn and infant health. Non-random use was observed in the preference for certain plant families during different stages of perinatal care.
SOUTH AFRICAN JOURNAL OF BOTANY
(2023)
Article
Biochemistry & Molecular Biology
Victor Sebastian-Perez, Paula Martinez de Iturrate, Montserrat Nacher-Vazquez, Luis Novoa, Concepcion Perez, Nuria E. Campillo, Carmen Gil, Luis Rivas
Summary: A study has identified novel inhibitors of Leishmania GSK-3 with strong antiparasitic activity and in vitro enzyme inhibition, laying the foundation for the development of potential drugs for leishmaniasis.
Article
Biochemical Research Methods
Chang Sun, Yangkun Cao, Jin-Mao Wei, Jian Liu
Summary: This study introduces an autoencoder-based method AEFS to predict drug-target interactions with spatial consistency constraints, maintaining the consistency between chemical properties and functions of drugs. Experimental comparisons show that AEFS is more robust for imbalanced data and performs significantly better in DTI prediction. Case studies further demonstrate its ability to discover latent DTIs.
Article
Chemistry, Multidisciplinary
Hyeohn Kim, Kyeong-Mi Bang, Heonjin Ha, Nam Heon Cho, Seok Daniel Namgung, Sang Won Im, Kang Hee Cho, Ryeong Myeong Kim, Won Il Choi, Yae-Chan Lim, Ji-Yeon Shin, Hyun Kyu Song, Nak-Kyoon Kim, Ki Tae Nam
Summary: Chiral inorganic nanomaterials, particularly chiral cobalt oxide nanoparticles synthesized with L- and D-Tyr-Tyr-Cys ligands, have been highlighted for their catalytic activity and biocompatibility. The conformation of the Tyr-Tyr-Cys peptide on the nanoparticle surfaces was identified by 2D NMR spectroscopy analysis, and the sequence effect of Tyr-Tyr-Cys developing chiral nanoparticles was analyzed. The role of the thiol group and carboxyl group of the Tyr-Tyr-Cys ligand in chirality evolution was demonstrated, with the circular dichroism responses being dramatically modulated under an external magnetic field due to the magnetic properties of chiral cobalt oxide nanoparticles.
Article
Biochemistry & Molecular Biology
Li Liu, Wen Song, Shijia Huang, Kai Jiang, Yoshitaka Moriwaki, Yichuan Wang, Yongfan Men, Dan Zhang, Xing Wen, Zhifu Han, Jijie Chai, Hongwei Guo
Summary: This study reveals that plant cell-surface peptide-receptor complexes can function as extracellular pH sensors, regulating plant growth and immunity. Acidic environment inhibits root meristem growth, while alkaline environment promotes immune response.
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.
Review
Pharmacology & Pharmacy
Susan Wray, Sarah Arrowsmith, Andrew Sharp
Summary: Although there are not many pregnancy-specific drugs, there are specific high-risk areas in obstetric care where unique pharmacological approaches have been established. These approaches have become the foundation for managing preterm birth, labor induction and augmentation, and postpartum hemorrhage. This review summarizes the existing evidence supporting and expanding these pharmacological approaches and their impact on clinical practice, including both established and emerging therapeutic options.
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY
(2023)
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
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
Entomology
Laura Regalado, Sara Sario, Rafael J. J. Mendes, Javier Valle, Peta J. J. Harvey, Catia Teixeira, Paula Gomes, David Andreu, Conceicao Santos
Summary: In this study, the biological activity of two underexplored spider venom peptides (J-atracotoxin-Hv1c and mu-theraphotoxin-Hhn2b) against adult D. suzukii flies was assessed, as well as the biological response of flies to these peptides through detoxification mechanisms. Results demonstrate that mu-theraphotoxin-Hhn2b enhanced fly longevity. Gene expression analysis suggests that detoxification and stress-related mechanisms are triggered in D. suzukii flies in response to treatment with these peptides. Our results highlight the potential of venom peptides to control D. suzukii and how to ultimately devise improved target-specific formulations.
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
Plant Sciences
Taj Muhammad, Wael E. Houssen, Louise Thomas, Cristina-Nicoleta Alexandru-Crivac, Sunithi Gunasekera, Marcel Jaspars, Ulf Goransson
Summary: The subtilisin-like macrocyclase PatGmac, produced by Prochloron didemni, is involved in the biosynthesis of patellamides. It recognizes and cyclizes precursor peptides with a specific recognition motif, resulting in the formation of the native macrocyclic patellamide. In this study, we investigate the potential use of PatGmac in cyclizing larger peptides, namely SFTI-1 and kalata B1.
JOURNAL OF NATURAL PRODUCTS
(2023)
Review
Chemistry, Multidisciplinary
Jessica Taylor, Andrew Sharp, Steve P. Rannard, Sarah Arrowsmith, Tom O. McDonald
Summary: The WHO estimates that 15 million babies are born preterm each year, resulting in 1 million infant mortalities and long-term health issues. While progress has been made in understanding the causes of preterm birth and developing therapeutic options such as progesterone or uterine contraction suppressants, the number of preterm births continues to rise. This review highlights the urgent need for alternative and improved therapeutic systems for preterm birth, specifically focusing on the potential of nanomedicine to enhance the efficacy and address current drawbacks of existing therapeutics. Different nanomedicines, including liposomes, lipid-based carriers, polymers, and nanosuspensions, are discussed, along with their significance in improving existing therapeutic agents in obstetrics. The review also explores the potential repurposing of other pharmaceutical agents with tocolytic properties for preterm birth treatment.
NANOSCALE ADVANCES
(2023)
Article
Biochemistry & Molecular Biology
Seyda Kara, Elif Ayazoglu Demir, Selcen Celik Uzuner, Muharrem Akcan
Summary: Anticancer peptide therapeutics have the potential to be effective in cancer treatment due to their specificity and tumor-homing abilities. This study aims to enhance the stability of the LyP-1 peptide in serum using cyclization and grafting strategies. The results show that the cyclic homodimer LyP-1 peptide exhibits extraordinary stability, and the retro grafted peptides also show improved stability.
INTERNATIONAL JOURNAL OF PEPTIDE RESEARCH AND THERAPEUTICS
(2023)