Review
Biochemistry & Molecular Biology
Angel Santiago, Dulce C. Guzman-Ocampo, Rodrigo Aguayo-Ortiz, Laura Dominguez
Summary: GS is a promising molecular target for AD treatment, with various inhibitors and modulators being evaluated. However, a global classification and visual representation of the chemical space for GS inhibitors and modulators is currently unavailable. This study conducted a 2D chemical space analysis to identify compounds with high molecular similarity and potential for finding new chemical structures through existing compound optimization.
ACS CHEMICAL NEUROSCIENCE
(2021)
Review
Biochemistry & Molecular Biology
Congkuan Song, Jinjin Zhang, Chenzhen Xu, Minglang Gao, Ning Li, Qing Geng
Summary: This article discusses the potential and problems of gamma-secretase and its inhibitors in cancer treatment, introducing gamma-secretase as a multi-substrate enzyme and its important role in cellular activities. The failure of current GSIs in clinical trials may be attributed to various factors.
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Meewhi Kim, Ilya Bezprozvanny
Summary: Proteolytic processing of amyloid precursor protein (APP) is critical in the pathogenesis of Alzheimer's disease (AD). Mutations in APP, PS1, or PS2 affect APP proteolysis by gamma-secretase and influence the levels of A beta 40 and A beta 42 peptides. This paper proposes a mechanistic hypothesis that may reconcile conflicting ideas and observations regarding the role of A beta peptides and gamma-secretase in AD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Dieter Petit, Manuel Hitzenberger, Matthias Koch, Sam Lismont, Katarzyna Marta Zoltowska, Thomas Enzlein, Carsten Hopf, Martin Zacharias, Lucia Chavez-Gutierrez
Summary: This study investigates the interactions between an imidazole-based GSM and its target gamma-secretase-APP, and reveals that a part of the modulator interacts with a binding site on gamma-secretase, triggering rearrangements and stabilizing enzyme-substrate interactions.
Review
Biochemistry & Molecular Biology
Joanna E. Luo, Yue-Ming Li
Summary: Alzheimer's disease is a common neurodegenerative disorder associated with the accumulation of A beta peptides. γ-secretase, the enzyme responsible for generating A beta peptides, has been a challenging drug target due to its complex structure and function. However, the development of γ-secretase modulators has opened up new possibilities for Alzheimer's disease treatment.
CELL AND BIOSCIENCE
(2022)
Review
Geriatrics & Gerontology
Jiaxuan Li, Xin Wu, Xin Tan, Shixin Wang, Ruisi Qu, Xiaofeng Wu, Zhouqing Chen, Zhong Wang, Gang Chen
Summary: This meta-analysis found that anti-A beta drugs do not have an effect on cognitive performance in AD patients, but monoclonal antibodies can delay cognitive decline. Development of other types of anti-A beta drugs should proceed with caution.
FRONTIERS IN AGING NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Matthias Koch, Thomas Enzlein, Shu-Yu Chen, Dieter Petit, Sam Lismont, Martin Zacharias, Carsten Hopf, Lucia Chavez-Gutierrez
Summary: This study explores the mechanism that controls the processing of the amyloid precursor protein (APP) by gamma-secretases, which is crucial in determining the length of amyloid-beta (A beta) peptides and their role in Alzheimer's disease (AD) pathogenesis. The researchers found that polar interactions established by the APPC99 ectodomain (ECD) play a key role in regulating the cleavage of APP by gamma-secretases. Increasing the hydrophobicity of APPC99-ECD attenuates substrate-driven product release and rescues the effects of Alzheimer's disease-associated pathogenic gamma-secretase and APP variants on A beta length. Furthermore, the study reveals that APPC99-ECD facilitates the production of longer A beta peptides caused by certain gamma-secretase inhibitors. These findings highlight the importance of the APPC99-ECD in regulating gamma-secretase activity and suggest it as a potential target for developing compounds that can selectively promote APP processing by these enzymes.
Article
Biochemistry & Molecular Biology
Meewhi Kim, Ilya Bezprozvanny
Summary: Proteolytic processing of amyloid precursor protein (APP) is critical in the pathogenesis of Alzheimer's disease (AD), with mutations causing increased Aβ42 production. Different conformations of gamma secretase with APP affect the amyloidogenic processing of APP. Analyzing protein structure can provide insights into the preferred processing of APP in different subcellular locations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Chen Jin, Jiaoni Wang, Yumeng Wang, Bojun Jia, Xuefei Guo, Guanghui Yang, Peng Xu, Paul Greengard, Rui Zhou, Yigong Shi
Summary: In this study, researchers discovered that GSAP-16K can modulate the cleavage of APP by gamma-secretase through both dilute phase and condensate formation. The dilute phase of GSAP-16K promotes the production of Aβ42, while the condensates of GSAP-16K reduce the cleavage of APP-C99. Additionally, GSAP-16K stably associates with APP-C99 through specific sequence elements. These findings provide mechanistic insights into the modulation of gamma-secretase activity and have implications for the development of potential therapeutics for diseases like Alzheimer's disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Neurosciences
Gunnar Nordvall, Johan Lundkvist, Johan Sandin
Summary: Recent clinical data have shown that removing A beta-amyloid plaques in early Alzheimer's disease can slow down disease progression. This progress validates the amyloid cascade hypothesis and highlights the importance of targeting A beta-amyloid for therapeutic purposes. It also suggests that reducing the production of amyloidogenic A beta can prevent the formation of A beta-pathology. Further research is needed to explore the potential of gamma-secretase modulators in preventing and treating Alzheimer's disease.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2023)
Article
Chemistry, Medicinal
Jiachen Wen, Dan Liu, Linxiang Zhao
Summary: Gamma-secretase is a large transmembrane protein complex consisting of four distinct units, which has garnered attention for its role in intramembrane proteolysis. The recent discovery of its atomic structure through cryo-EM has enhanced our understanding of its physiological functions and facilitated the development of novel molecules targeting gamma-secretase. This review focuses on the latest progress of gamma-secretase inhibitors and modulators in clinical and preclinical stages, as well as their potential applications in various biological indications.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Pardeep Yadav, Yeon-Hee Lee, Hrithika Panday, Shubham Kant, Neha Bajwa, Ritika Parashar, Saurabh Kumar Jha, Niraj Kumar Jha, Parma Nand, Sang-Soo Lee, Abhimanyu Kumar Jha
Summary: Alzheimer's disease is a deadly brain disorder characterized by brain shrinkage and dementia. Studies have found evidence of fungal and bacterial infections in the brain tissue of AD patients, which may contribute to neuroinflammation and neurodegeneration. Pathogens such as herpes simplex virus and periodontal bacteria can cross the blood-brain barrier and play a role in the onset of AD.
CURRENT ISSUES IN MOLECULAR BIOLOGY
(2022)
Article
Neurosciences
Can Zhang, Shivangi M. Inamdar, Swathi Swaminathan, Daniel R. Marenda, Aleister J. Saunders
Summary: This study identifies a loss-of-function mechanism of Ubiquilin-1 in Alzheimer's disease and highlights the significance of targeting Ubiquilin-1-mediated protein quality control as a potential therapeutic strategy.
FRONTIERS IN NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Whendy Contreras, J. Fernando Bazan, Torben Mentrup
Summary: F rey1 has been identified as an inhibitory protein of SPPL2c, and its specific motif can be transplanted to the substrate PLN to generate inhibitors for this enzyme. The findings suggest a mechanism for inhibiting aspartic I-CLIPs and provide potential tools for targeted drug development.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Siling Liu, Zhongyu Zhang, Lianwei Li, Li Yao, Zhanshan Ma, Jiali Li
Summary: PTPRT is downregulated in the brains of AD patients and mouse models, and its cleavage releases PICD which translocates to the nucleus and inhibits pSTAT3 accumulation, leading to neuronal cell death. Overexpression of PICD affects gene expression related to synapse formation, cell adhesion, and protein dephosphorylation. Furthermore, PICD overexpression improves synaptic function, reduces phospho-STAT3(Y705) and amyloid beta production in APP/PS1 mice, and partially rescues behavioral deficits.
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)