Article
Multidisciplinary Sciences
Eva Pauwels, Neesha R. Shewakramani, Brent De Wijngaert, Anita Camps, Becky Provinciael, Joren Stroobants, Kai -Uwe Kalies, Enno Hartmann, Piet Maes, Kurt Vermeire, Kalyan Das
Summary: During cotranslational translocation, the signal peptide of a nascent chain binds Sec61 translocon to initiate protein transport through the endoplasmic reticulum (ER) membrane. Our cryo-electron microscopy structure of ribosome-Sec61 shows binding of an ordered heterotetrameric translocon-associated protein (TRAP) complex, in which TRAP-gamma is anchored at two adjacent positions of 28S ribosomal RNA and interacts with ribosomal protein L38 and Sec61 alpha/gamma. Four transmembrane helices (TMHs) of TRAP-gamma cluster with one C-terminal helix of each alpha, 13, and delta subunits.
Article
Biochemistry & Molecular Biology
Eva Pauwels, Becky Provinciael, Anita Camps, Enno Hartmann, Kurt Vermeire
Summary: One of the substrates for the ER translocation inhibitor CADA is DNAJC3, which is a chaperone involved in the unfolded protein response. This study investigates the impact of altered DNAJC3 protein levels on the inhibitory activity of CADA. The results show that higher DNAJC3 expression enhances the sensitivity of certain proteins to CADA, and reducing DNAJC3 levels slows down the clearance of CADA-stalled substrates, leading to increased translocation into the ER lumen.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biology
Mark Sicking, Martina Zivna, Pratiti Bhadra, Veronika Baresova, Andrea Tirincsi, Drazena Hadzibeganovic, Katerina Hodanova, Petr Vyletal, Jana Sovova, Ivana Jedlickova, Martin Jung, Thomas Bell, Volkhard Helms, Anthony J. Bleyer, Stanislav Kmoch, Adolfo Cavalie, Sven Lang
Summary: The idiopathic SEC61A1 missense mutations have been found to cause a localized kidney disease by impairing protein transport and calcium ion homeostasis. Treatment with the molecular chaperone phenylbutyrate can reverse these defects.
LIFE SCIENCE ALLIANCE
(2022)
Article
Immunology
Elisa Claeys, Eva Pauwels, Stephanie Humblet-Baron, Becky Provinciael, Dominique Schols, Mark Waer, Ben Sprangers, Kurt Vermeire
Summary: The small molecule CADA has demonstrated potent immunosuppressive effects on both CD4 and CD8 T cells, with a particularly prominent impact on CD8 T cells. It exerts its effects through mechanisms such as inhibiting cytokine secretion, regulating protein expression, and reducing T cell functions.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Eva Pauwels, Ralf Schuelein, Kurt Vermeire
Summary: The process of protein translocation across the ER is mediated by the Sec61 translocon complex, which is challenging to purify and reconstitute, making it difficult to screen for small molecule inhibitors. However, these inhibitors have potential as valuable tools in cell biology and as novel anticancer drugs. Recent screening strategies may also help in identifying new antibiotic drugs targeting the bacterial Sec61 complex counterpart, SecYEG.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Pratiti Bhadra, Volkhard Helms
Summary: Recent molecular modeling and simulation studies have focused on the dynamics and mechanisms of the Sec translocon, exploring the process of protein translocation into the endoplasmic reticulum and bacterial periplasm. Computational studies have investigated the conformational dynamics of the translocon in various states and addressed mechanistic issues such as membrane insertion and peptide recognition. Additionally, simulations have examined how accessory proteins impact Sec61 conformation during translation pathways.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Computer Science, Interdisciplinary Applications
Fatemeh Sabzian-Molaei, Mohammad Amin Ahmadi, Zahra Nikfarjam, Mohammad Sabzian-Molaei
Summary: This study aimed to design mutant peptides that could block the interaction between gp120 and the CD4 receptor on host cells, thus preventing HIV-1 infection. Three peptides showed potential as HIV inhibitors.
MEDICAL & BIOLOGICAL ENGINEERING & COMPUTING
(2023)
Review
Biochemistry & Molecular Biology
A. Manuel Liaci, Friedrich Forster
Summary: Cleavable and non-cleavable signal sequences target a quarter of the human proteome to the ER. Interaction between these signal sequences and ER targeting machinery determines protein location and translocation fidelity, as discussed in recent insights from structural biology.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Mark Sicking, Martin Jung, Sven Lang
Summary: Various landmark studies have illuminated the structures and functions of the Sec61/SecY complex across all biological domains, showcasing the conserved nature of this ancestral protein translocase. The eukaryotic Sec61 complex facilitates the transfer of precursor proteins into or across the endoplasmic reticulum membrane, accompanied by dynamically recruited auxiliary proteins. Utilizing TRAP and Sec62/Sec63 complexes as models, the study aimed to detect interactions of membrane proteins in living mammalian cells under physiological conditions, revealing multiple protein-protein interactions of diverse topological layouts.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Ziqi Lyu, Melody M. Sycks, Mateo F. Espinoza, Khanh K. Nguyen, Maureen R. Montoya, Cheska M. Galapate, Liangyong Mei, Joseph C. Genereux
Summary: Protein mistargeting can threaten cellular protein homeostasis, but current measurement methods are difficult to apply to living cells. This study uses genetically encoded peroxidases to investigate protein import into the endoplasmic reticulum (ER) and demonstrates that proximity labeling is an effective strategy for characterizing factors that influence ER protein import in living cells.
ACS CHEMICAL BIOLOGY
(2022)
Article
Cell Biology
Hannah L. Itell, Daryl Humes, Julie Overbaugh
Summary: This study identifies new ISGs that inhibit HIV and confirms the role of certain factors in IFN restriction in T cells. The findings demonstrate the multifaceted nature of IFN restriction against HIV and establish a screening model for identifying HIV-restricting ISGs.
Article
Allergy
Hanga Reka Horvath, David Szilagyi, Noemi Andrasi, Zsuzsanna Balla, Beata Visy, Henriette Farkas
Summary: This study aimed to assess the occurrence of hypersensitivity reactions in the Hungarian C1-INH-HAE population. A questionnaire consisting of 112 questions was filled out by 106 patients, and the results showed that 63.2% of patients reported hypersensitivity symptoms. The most common triggers were pollen, contact sensitivity, and food. Some patients experienced improvement in symptoms, while others remained the same. In a small percentage of patients, a C1-INH-HAE attack worsened hypersensitivity symptoms or was provoked by contact with the allergen.
WORLD ALLERGY ORGANIZATION JOURNAL
(2023)
Article
Biochemistry & Molecular Biology
Liezel A. Lumangtad, Elisa Claeys, Sunil Hamal, Amarawan Intasiri, Courtney Basrai, Expedite Yen-Pon, Davison Beenfeldt, Kurt Vermeire, Thomas W. Bell
BIOORGANIC & MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Karoline Berger, Eva Pauwels, Gabrielle Parkinson, Goran Landberg, Truc Le, Violeta G. Demillo, Liezel A. Lumangtad, Dylan E. Jones, Md Azizul Islam, Ryan Olsen, Topprasad Kapri, Amarawan Intasiri, Kurt Vermeire, Sara Rhost, Thomas W. Bell
Summary: Cyclotriazadisulfonamide (CADA) compounds selectively target CD4 and sortilin proteins, inhibiting progranulin-induced dedifferentiation and cancer stem cell proliferation in breast cancer. Among the new compounds, TL020, TL023, VGD071, and LAL014 show significant effects in reducing progranulin-induced breast cancer stem cell propagation. VGD071 is identified as a promising candidate for future studies using mouse breast cancer models based on solubility, potency, and cytotoxicity comparisons.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Rameez Ali, Sreenivasa Anugu, Reena Chawla, Violeta G. Demillo, Florian Goulinet-Mateo, Sagar Gyawali, Sunil Hamal, Dylan E. Jones, Katrin Lamprecht, Truc Le, Liezel A. Lumangtad, Nicholas C. Pflug, Alekhya Sama, Emily D. Scarbrough, Thomas W. Bell
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)