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)
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)
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.
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
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
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.
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)
Article
Neurosciences
Masato Maesako, Mei C. Q. Houser, Yuliia Turchyna, Michael S. Wolfe, Oksana Berezovska
Summary: In this study, we used a novel imaging method to visualize the subcellular compartment where γ-secretase primarily cleaves C99 to generate Aβ in mouse cortical neurons. Our findings suggest that γ-secretase processes C99 mainly in low-pH compartments and Aβ is accumulated in the same subcellular loci. Additionally, we found a functional correlation between endo-lysosomal pH and cellular γ-secretase activity.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Urszula Orzel, Jakub Jakowiecki, Krzysztof Mlynarczyk, Slawomir Filipek
Summary: The study showed that at high cholesterol levels, Aβ(45) was more flexible in the binding site of presenilin than Aβ(43), but the active site of presenilin at the C-terminal part of Aβ(45) was more compact, which could promote processing of this substrate. Cholesterol binding sites at low and high concentrations were also mapped, independent of typical cholesterol binding motifs.
Review
Chemistry, Medicinal
Joao P. S. Ferreira, Helio M. T. Albuquerque, Susana M. Cardoso, Artur M. S. Silva, Vera L. M. Silva
Summary: Alzheimer's disease (AD) is a major cause of dementia worldwide, with no disease-modifying treatments currently available. Distinct pharmacological targets like Acetylcholinesterase (AChE) and B-secretase-1 (BACE-1) have been explored for AD treatment. Research is focused on developing multi-target directed ligands as an alternative approach to single-target drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Editorial Material
Biochemistry & Molecular Biology
Daniel R. Dries, Gang Yu
Summary: Research showed that gamma-secretase is a potential therapeutic target for Alzheimer's disease, and provided new opportunities for treatment.
Article
Biochemistry & Molecular Biology
Alicia Ioppolo, Melissa Eccles, David Groth, Giuseppe Verdile, Mark Agostino
Summary: gamma-Secretase is an important intramembrane aspartyl protease that regulates cell physiology by cleaving multiple transmembrane proteins. Aberrant activity of gamma-Secretase is implicated in various diseases. Recent structural evidence provides insight into the binding of gamma-Secretase inhibitors and modulators, facilitating rational drug design. This study successfully identified known inhibitors and modulators and applied screening strategies to discover novel small molecules targeting gamma-Secretase.
Article
Chemistry, Medicinal
Simeon Bowers, Gary D. Probst, Anh P. Truong, Roy K. Hom, Andrei W. Konradi, Hing L. Sham, Albert W. Garofalo, Karina Wong, Erich Goldbach, Kevin P. Quinn, John-Michael Sauer, William Wallace, Lan Nguyen, Susanna S. Hemphill, Michael P. Bova, Guriqbal S. Basi
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2009)
Article
Chemistry, Medicinal
Xiaocong M. Ye, Andrei W. Konradi, Jenifer Smith, Danielle L. Aubele, Albert W. Garofalo, Jennifer Marugg, Marty L. Neitzel, Chris M. Semko, Hing L. Sham, Minghua Sun, Anh P. Truong, Jing Wu, Hongbin Zhang, Erich Goldbach, John-Michael Sauer, Elizabeth F. Brigham, Michael Bova, Guriqbal S. Basi
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2010)
Article
Chemistry, Medicinal
Danielle L. Aubele, Anh P. Truong, Darren B. Dressen, Gary D. Probst, Simeon Bowers, Matthew N. Mattson, Chris M. Semko, Minghua Sun, Albert W. Garofalo, Andrei W. Konradi, Hing L. Sham, Wes Zmolek, Karina Wong, Erich Goldbach, Kevin P. Quinn, John-Michael Sauer, Elizabeth F. Brigham, William Wallace, Lan Nguyen, Michael P. Bova, Susanna S. Hemphill, Guriqbal Basi
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2011)
Article
Chemistry, Medicinal
Maurizio Franzini, Xiaocong M. Ye, Marc Adler, Danielle L. Aubele, Albert W. Garofalo, Shawn Gauby, Erich Goldbach, Gary D. Probst, Kevin P. Quinn, Pam Santiago, Hing L. Sham, Danny Tam, Anh Truong, Zhao Ren
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2013)
Article
Chemistry, Medicinal
Albert W. Garofalo, Marc Adler, Danielle L. Aubele, Elizabeth F. Brigham, David Chian, Maurizio Franzini, Erich Goldbach, Grace T. Kwong, Ruth Motter, Gary D. Probst, Kevin P. Quinn, Lany Ruslim, Hing L. Sham, Danny Tam, Pearl Tanaka, Anh P. Truong, Xiaocong M. Ye, Zhao Ren
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2013)
Article
Chemistry, Medicinal
Albert W. Garofalo, Marc Adler, Danielle L. Aubele, Simeon Bowers, Maurizio Franzini, Erich Goldbach, Colin Lorentzen, R. Jeffrey Neitz, Gary D. Probst, Kevin P. Quinn, Pam Santiago, Hing L. Sham, Danny Tam, Anh P. Truong, Xiaocong M. Ye, Zhao Ren
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2013)
Article
Chemistry, Medicinal
Albert William Garofalo, Jacek Jerzy Jagodzinski, Andrei William Konradi, Raymond Anthony Ng, Christopher Michael Semko, Hing Leung Sham, Minghua Sun, Xiaocong Michael Ye
CHEMICAL & PHARMACEUTICAL BULLETIN
(2012)
Review
Chemistry, Medicinal
Albert W. Garofalo
EXPERT OPINION ON THERAPEUTIC PATENTS
(2008)
Article
Chemistry, Medicinal
Albert W. Garofalo, Jacob Schwarz, Kerry Zobel, Claudia Beato, Silvia Bernardi, Federica Budassi, Laura Caberlotto, Peng Gao, Cristiana Griffante, Xinying Liu, Marco Migliore, Feifei Qiao, Fabio Maria Sabbatini, Anna Sava, Mingliang Zhang, Holly J. Carlisle
Summary: The G2019S variant of LRRK2 is associated with Parkinson's disease (PD) and causes an increase in kinase activity. A series of novel kinase inhibitors have been discovered that selectively inhibit the phosphorylation of LRRK2 in the mouse brain, offering potential for precision medicine in future PD therapeutics.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Medicinal
Darren Dressen, Albert W. Garofalo, Jon Hawkinson, Dennis Hom, Jacek Jagodzinski, Jennifer L. Marugg, Martin L. Neitzel, Michael A. Pleiss, Balazs Szoke, Jay S. Tung, David W. G. Wone, Jing Wu, Heather Zhang
JOURNAL OF MEDICINAL CHEMISTRY
(2007)
Article
Pharmacology & Pharmacy
Jon E. Hawkinson, Balazs G. Szoke, Albert W. Garofalo, Dennis S. Hom, Hongbing Zhang, Mark Dreyer, Juri Y. Fukuda, Linda Chen, Bhushan Samant, Stellanie Simmonds, Karla P. Zeitz, Angie Wadsworth, Anna Liao, Raymond A. Chavez, Wes Zmolek, Lany Ruslim, Michael P. Bova, Ryan Holcomb, Eduardo R. Butelman, Mei-Chuan Ko, Annika B. Malmberg
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2007)
Article
Chemistry, Medicinal
AW Garofalo, DWG Wone, A Phuc, JE Audia, CA Bales, HF Dovey, DB Dressen, B Folmer, EG Goldbach, AC Guinn, LH Latimer, TE Mabry, JS Nissen, MA Pleiss, S Sohn, EC Thorsett, JS Tung, J Wu
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2002)
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)
