Article
Cell Biology
Mengrong Li, Yiqiong Bao, Ran Xu, Miaomiao Li, Lili Xi, Jingjing Guo
Summary: The identification and development of non-peptide allosteric modulators for PTH1R have gained attention. It has been found that a negative allosteric modulator (NAM) inhibits the activation of PTH1R, but the mechanism is unclear. Molecular dynamics simulations and analytical approaches reveal that NAM destabilizes the PTH1R-PTH-spep/qpep complexes, weakens PTH/peps-PTH1R binding, and reduces intra- and inter-molecular couplings in PTH1R. Compared with positive allosteric effects induced by extracellular Ca2+, the negative allosteric regulator significantly reduces the correlation between PTH and G-protein binding sites. These findings contribute to the development of new therapeutics for diseases caused by PTH1R abnormal activation.
Article
Neurosciences
Alessandra Porcu, Rafaela Mostallino, Valeria Serra, Miriam Melis, Valeria Sogos, Sarah Beggiato, Luca Ferraro, Fabrizio Manetti, Beatrice Gianibbi, Bernhard Bettler, Federico Corelli, Claudia Mugnaini, M. Paola Castelli
Summary: This study characterized the negative allosteric modulator COR758 for GABA(B) receptors, showing its potential as a therapeutic candidate by inhibiting G protein signaling. COR758 may serve as a scaffold for developing additional NAMs for therapeutic intervention by interacting with an allosteric binding site of GABA(B) receptors.
Article
Medicine, Research & Experimental
Seungkirl Ahn, Harm Maarsingh, Julia K. L. Walker, Samuel Liu, Akhil Hegde, Hyeje C. Sumajit, Alem W. Kahsai, Robert J. Lefkowitz
Summary: This article investigates the potential of β2AR-selective positive allosteric modulators (PAMs) in the treatment of asthma and other obstructive respiratory diseases. The results demonstrate that these PAMs can enhance the binding and downstream signaling of β2-agonists to β2ARs in guinea pigs and humans, thereby promoting bronchodilation and protection.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Multidisciplinary Sciences
Shun Kaneko, Shunsuke Imai, Nobuaki Asao, Yutaka Kofuku, Takumi Ueda, Ichio Shimada
Summary: This study reveals a novel mechanism of GPCR activation and the potential of allosteric modulators to enhance GPCR activity. The use of solution NMR analysis provides insights into the structural changes and equilibrium of GPCRs, shedding light on the rational development of next-generation GPCR-targeting therapeutics.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Joshua D. Frenster, Hediye Erdjument-Bromage, Gabriele Stephan, Niklas Ravn-Boess, Shuai Wang, Wenke Liu, Devin Bready, Jordan Wilcox, Bjorn Kieslich, Manuel Jankovic, Caroline Wilde, Susanne Horn, Norbert Strater, Ines Liebscher, Torsten Schoneberg, David Fenyo, Thomas A. Neubert, Dimitris G. Placantonakis
Summary: This study identifies PTK7 as an extracellular binding partner of GPR133 in glioblastoma, and shows that PTK7 enhances GPR133 signaling by binding to the N-terminal fragment of GPR133. This interaction is potentially relevant to the pathogenesis of glioblastoma.
Review
Chemistry, Multidisciplinary
Keith M. Olson, John R. Traynor, Andrew Alt
Summary: Allosteric modulators (AMs) of G-protein coupled receptors (GPCRs) present desirable drug targets due to their potential to produce fewer on-target side effects and improved selectivity compared to orthosteric drugs. Peptides and proteins, deriving from endogenous protein-protein interactions, intramolecular receptor contacts, endogenous peptides, and exogenous libraries, serve as underappreciated sources for identifying AM leads, offering advantages such as high affinity and bioactivity along with disadvantages like poor metabolic stability. Peptidomimetics combine the advantages of both peptides and small molecules, mimicking peptide chemical features responsible for bioactivity while enhancing druggability.
FRONTIERS IN CHEMISTRY
(2021)
Article
Immunology
Tehila Mizrachi, Oshrit Marsha, Karen Brusin, Yael Ben-David, Ganesh A. Thakur, Adi Vaknin-Dembinsky, Millet Treinin, Talma Brenner
Summary: GAT107, an ago-PAM of alpha 7 nAChR, can significantly reduce disease severity and neuroinflammation in EAE by activating the receptor, leading to decreased pro-inflammatory cytokine production and increased anti-inflammatory cytokine IL-10. It also alters the expression of immune cell markers and directly activates alpha 7 nAChR in immune cells of MS patients and healthy donors.
JOURNAL OF NEUROINFLAMMATION
(2021)
Article
Biochemistry & Molecular Biology
Junghyun L. Suh, Daniel Bsteh, Bryce Hart, Yibo Si, Tyler M. Weaver, Carina Pribitzer, Roy Lau, Shivani Soni, Heather Ogana, Justin M. Rectenwald, Jacqueline L. Norris, Stephanie H. Cholensky, Cari Sagum, Jessica D. Umana, Dongxu Li, Brian Hardy, Mark T. Bedford, Shannon M. Mumenthaler, Heinz-Josef Lenz, Yong-Mi Kim, Gang Greg Wang, Ken H. Pearce, Lindsey James, Dmitri B. Kireev, Catherine A. Musselman, Stephen Frye, Oliver Bell
Summary: CBX proteins are cell-type-specific paralogous chromobox proteins that repress developmental genes. We have identified a potent positive allosteric modulator (PAM), UNC7040, for CBX8, which disrupts its binding to H3K27me3 and enhances interactions with nucleic acids. Treatment with UNC7040 efficiently and selectively removes CBX8-containing PRC1 from chromatin, resulting in gene desilencing and reduced proliferation in cancer cells.
CELL CHEMICAL BIOLOGY
(2022)
Article
Neurosciences
Saad B. Hannan, Reka Penzinger, Ginte Mickute, Trevor G. Smart
Summary: GABA receptors, particularly GABABRs, are important therapeutic targets for neurodevelopmental and neuropsychiatric disorders. However, a widely used positive allosteric modulator, CGP7930, was found to have effects on both GABABRs and GABAARs, as well as GIRK channels, making it unsuitable as a specific GABABR PAM.
Article
Neurosciences
Kiran Sapkota, Erica S. Burnell, Mark W. Irvine, Guangyu Fang, Dinesh Y. Gawande, Shashank M. Dravid, David E. Jane, Daniel T. Monaghan
Summary: The study characterizes a novel NMDAR antagonist, UBP792, which displays partial subtype-selectivity and inhibits NMDAR responses by reducing the potency and efficacy of L-glutamate and glycine. It acts non-competitively, with activity independent of voltage and affected by pH, and potentially stabilizes different channel conformations to inhibit NMDAR function. This expands the possibilities for developing NMDAR modulators with appropriate selectivity for therapeutic indications.
Article
Multidisciplinary Sciences
Michael Ippolito, Francesco De Pascali, Nathan Hopfinger, Konstantin E. Komolov, Daniela Laurinavichyute, Poli Adi Narayana Reddy, Leon A. Sakkal, Kyle Z. Rajkowski, Ajay P. Nayak, Justin Lee, Jordan Lee, Gaoyuan Cao, Preston S. Donover, Melvin Reichman, Steven S. An, Joseph M. Salvino, Raymond B. Penn, Roger S. Armen, Charles P. Scott, Jeffrey L. Benovic
Summary: A negative allosteric modulator, DFPQ, was found to selectively inhibit beta-arrestin recruitment to beta(2)AR without affecting its coupling to Gs. This may provide a strategy to improve the functional consequences of beta(2)AR activation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Chemistry, Medicinal
Sumanta Garai, Luciana M. Leo, Anna-Maria Szczesniak, Dow P. Hurst, Peter C. Schaffer, Ayat Zagzoog, Tallan Black, Jeffrey R. Deschamps, Elke Miess, Stefan Schulz, David R. Janero, Alex Straiker, Roger G. Pertwee, Mary E. Abood, Melanie E. M. Kelly, Patricia H. Reggio, Robert B. Laprairie, Ganesh A. Thakur
Summary: By introducing a methyl group at the a-position of the nitro group, the greater potency and efficacy of the 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator was achieved, offering safer therapeutic candidates for glaucoma and potentially other diseases. The diastereoselective CB1R-allosteric modulator interaction was demonstrated for the first time, with one enantiomer showing improved potency and the other biased towards specific signaling pathways. Exploiting G-protein biased CB1R-allosteric modulation shows promise for developing more effective and targeted treatments.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Neurosciences
Sakiko Taniguchi, Jacob R. Stolz, Geoffrey T. Swanson
Summary: Perampanel (PMP) has been found to inhibit both AMPAR and KARs, suggesting that its clinical actions may arise from selective inhibition of different glutamate receptor signaling pathways.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Multidisciplinary Sciences
Guohui Zhang, Xianjin Xu, Zhiguang Jia, Yanyan Geng, Hongwu Liang, Jingyi Shi, Martina Marras, Carlota Abella, Karl L. Magleby, Jonathan R. Silva, Jianhan Chen, Xiaoqin Zou, Jianmin Cui
Summary: Researchers have discovered a compound, BC5, that interacts with the CTD-VSD interface and specifically modulates the Ca2+ dependent activation mechanism. BC5 can activate the channel in the absence of Ca2+ binding, but Ca2+ binding inhibits BC5 effects. This study reveals the importance of the CTD-VSD interaction in the Ca2+ activation mechanism and provides insights for allosteric agonists to modulate BK channel activation.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
David F. Lee, Matan Geron, Gregory Scherrer
Summary: The structural studies of a positive allosteric modulator of the adenosine A(1) receptor reveal the mechanisms by which stabilizing the GPCR-G protein complex bound to its endogenous agonist results in analgesic efficacy in an animal model of neuropathic pain.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2021)
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)