Article
Multidisciplinary Sciences
Kimberly Gomez, Harrison J. Stratton, Paz Duran, Santiago Loya, Cheng Tang, Aida Calderon-Rivera, Liberty Francois-Moutal, May Khanna, Cynthia L. Madura, Shizhen Luo, Bryan McKiver, Edward Choi, Dongzhi Ran, Lisa Boinon, Samantha Perez-Miller, M. Imad Damaj, Aubin Moutal, Rajesh Khanna
Summary: This study demonstrates that the CRMP2 regulatory sequence (CRS) is a targetable region for the treatment of chronic neuropathic pain. Cell-penetrant decoy peptides targeting NaV1.7 CRS can reduce NaV1.7 currents and trafficking, reverse mechanical allodynia, and do not produce motor impairment or alter physiological pain sensation. Furthermore, packaging the NaV1.7-CRS encoding plasmid into an AAV virus allows for gene therapy to reverse and prevent mechanical allodynia.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Pharmacology & Pharmacy
Fangyu Du, Ruolin Cao, Lu Chen, Jianwen Sun, Yajie Shi, Yang Fu, Bruce D. Hammock, Zhonghui Zheng, Zhongbo Liu, Guoliang Chen
Summary: A new memantyl urea derivative, A20, was identified as a potent sEH inhibitor that can alleviate pain and improve the health status of rats, making it a promising candidate for the treatment of neuropathic pain.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Chemistry, Medicinal
Narayan Karanjule, Noriyuki Hayashi, Sayaka Suzuki, Toshifumi Tsuda, Eri Tokumaru, Kyosuke Tanaka, Hiroko Kimoto, Yuki Domon, Sakiko Takahashi, Kazufumi Kubota, Yutaka Kitano, Tomihisa Yokoyama, Ryuta Koishi, Chie Fujiwara, Shinichi Inaba, Daigo Asano, Tomoko Sakakura, Kiyoshi Takasuna, Tsuyoshi Shinozuka
Summary: A novel class of potent Na(V)1.7 inhibitors, N-aryl indoles, were discovered by investigating the replacement of diaryl ether in compound I. The introduction of the 3-methyl group was crucial for high Na(V)1.7 inhibitory activity. Compound 2e demonstrated high in vitro potencies against both human and mouse Na(V)1.7 with high selectivity and showed potent efficacy in PSL mice with excellent pharmacokinetics.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Multidisciplinary
Dengqi Xue, Yani Liu, Yilin Zheng, Heling Niu, Liying Dong, Xiangshuo Ouyang, Siyu Song, Denggao Zhang, Qianwei Ge, Kewei Wang, Liming Shao
Summary: Three novel series of alpha-aminoamides derivatives were synthesized based on ralfinamide, and their inhibitory activities against Nav1.7 were evaluated. The most potent compound 19h exhibited significantly higher activity than ralfinamide, and the structure-activity relationship investigation provided a strategy for improving the Nav1.7 inhibition of ralfinamide analogues.
CHINESE CHEMICAL LETTERS
(2022)
Article
Biology
Marc Kschonsak, Christine C. Jao, Christopher P. Arthur, Alexis L. Rohou, Philippe Bergeron, Daniel F. Ortwine, Steven J. McKerrall, David H. Hackos, Lunbin Deng, Jun Chen, Tianbo Li, Peter S. Dragovich, Matthew Volgraf, Matthew R. Wright, Jian Payandeh, Claudio Ciferri, John C. Tellis
Summary: The Na(V)1.7 channel has been identified as a potential analgesic target, but current channel-blocking drugs lack selectivity among the nine Na(V) channel subtypes. A recent study using cryo-EM revealed a new binding mechanism of the inhibitor GDC-0310 to Na(V)1.7, and a novel hybrid inhibitor series was designed to bridge the binding pockets of aryl- and acylsulfonamide inhibitors. This study highlights the power of cryo-EM methods in drug target discovery and emphasizes the importance of the membrane bilayer in optimizing selective Na(V) channel modulators.
Article
Cell Biology
Richard L. Kraus, Fuqiang Zhao, Parul S. Pall, Dan Zhou, Joshua D. Vardigan, Andrew Danziger, Yuxing Li, Christopher Daley, Jeanine E. Ballard, Michelle K. Clements, Rebecca M. Klein, Marie A. Holahan, Thomas J. Greshock, Ronald M. Kim, Mark E. Layton, Christopher S. Burgey, Jordi Serra, Darrell A. Henze, Andrea K. Houghton
Summary: Humans with mutations in the Na(v)1.7 channel gene can either be insensitive to pain or suffer from inherited pain syndromes. Clinical studies using Na(v)1.7 inhibitors have not shown significant pain relief, leading researchers to develop rhesus macaque models to measure target modulation and efficacy.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Ying Chen, Xiangyin Chi, Hongjuan Zhang, Yu Zhang, Luyao Qiao, Jinwen Ding, Yanxing Han, Yuan Lin, Jiandong Jiang
Summary: In this study, a virtual screening method was used to identify potential candidates targeting ZIKV replication enzyme from two drug libraries. Posaconazole was confirmed to effectively inhibit ZIKV replication by binding with the key amino acid D666. This study provides posaconazole as a potential anti-ZIKV agent with stronger inhibitory activity than chloroquine.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Jerome Montnach, Stephan De Waard, Sebastien Nicolas, Sophie Burel, Nancy Osorio, Claude Zoukimian, Massimo Mantegazza, Rachid Boukaiba, Remy Beroud, Michel Partiseti, Patrick Delmas, Celine Marionneau, Michel De Waard
Summary: By taking advantage of the high affinity properties of ProTx II, new tagged analogues were designed for cell distribution and biochemical characterization purposes. Two of these analogues, Biot-ProTx II and ATTO488-ProTx II, closely mimic the pharmacological properties of unlabelled ProTx II, while other analogues remain high affinity blockers of Na(v)1.7.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Review
Pharmacology & Pharmacy
David A. Eagles, Chun Yuen Chow, Glenn F. King
Summary: This review examines the role of Na(V)1.7 channels in nociception, their history as a therapeutic target, and the challenges in developing potent inhibitors. Despite significant progress in drug development, effective analgesia remains elusive in clinical trials.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Menglan Luo, Qian Wu, Yueyue Yang, Lin Sun, Xiajuan Huan, Changqing Tian, Bing Xiong, Zehong Miao, Yingqing Wang, Danqi Chen
Summary: Bromodomain and extraterminal domain (BET) subfamily members are potential targets for cancer treatment. This study presents a series of novel bivalent inhibitors with short and hydrophilic linkers, which exhibit improved activities and pharmacokinetic properties.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Elsie C. Yu, Joey L. Methot, Xavier Fradera, Charles A. Lesburg, Brian M. Lacey, Phieng Siliphaivanh, Ping Liu, Dustin M. Smith, Zangwei Xu, Jennifer A. Piesvaux, Shuhei Kawamura, Haiyan Xu, J. Richard Miller, Mark Bittinger, Alexander Pasternak
Summary: The study optimized the structure of kinase inhibitor 4 through a systematic two-dimensional diversity screen of pyrazolopyridines, identifying potent and selective compounds. Further optimization led to the identification of potent and selective reverse indazole inhibitor 36 that exhibited low clearance and notable bioavailability in in vivo rat studies, inhibiting phosphorylation of adaptor protein SLP76 in human PBMC.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Medicine, Research & Experimental
Shingo Nakamura, Takahiro Nonaka, Shuji Komatsu, Toshihiko Yamada, Tatsuo Yamamoto
Summary: The mechanism by which acetaminophen produces its analgesic effects involves the activation of the spinal 5-hydroxytryptamine (5-HT) receptor, possibly through the metabolite N-arachidonoylphenolamine (AM404). Both oral acetaminophen and intracerebroventricular AM404 induce spinal 5-HT release and analgesic effects in rat formalin tests, but with differing interactions with 5-HT receptor antagonists.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Immunology
Henrique Ballassini Abdalla, Marcelo Henrique Napimoga, Juliana Maia Teixeira, Carlos Antonio Trindade-da-Silva, Victor Luis Pieroni, Fernanda Souto Maior dos Santos Araujo, Bruce D. Hammock, Juliana Trindade Clemente-Napimoga
Summary: This study demonstrates that pre-treatment with a local soluble epoxide hydrolase (sEH) inhibitor can prevent inflammatory hyperalgesia in the temporomandibular joint (TMJ) of rats, and has both analgesic and anti-inflammatory effects.
INFLAMMOPHARMACOLOGY
(2022)
Article
Neurosciences
Bao-Wen Liu, Jin Zhang, Yi-Shun Hong, Ning-Bo Li, Yi Liu, Mi Zhang, Wen-Yao Wu, Hua Zheng, Angelika Lampert, Xian-Wei Zhang
Summary: Currently, the mechanisms underlying chronic post-surgical pain (CPSP) are not fully understood, but research suggests that nerve growth factor (NGF) may lead to long-term dysregulation of Nav1.7, contributing to CPSP development. The sustained upregulation of Nav1.7 triggered by NGF plays a role in CPSP progression, while alleviating the dysregulation of Nav1.7 in peripheral nociceptors could be a strategy for preventing CPSP.
MOLECULAR NEUROBIOLOGY
(2021)
Article
Multidisciplinary Sciences
Kris M. White, Romel Rosales, Soner Yildiz, Thomas Kehrer, Lisa Miorin, Elena Moreno, Sonia Jangra, Melissa B. Uccellini, Raveen Rathnasinghe, Lynda Coughlan, Carles Martinez-Romero, Jyoti Batra, Ajda Rojc, Mehdi Bouhaddou, Jacqueline M. Fabius, Kirsten Obernier, Marion Dejosez, Maria Jose Guillen, Alejandro Losada, Pablo Aviles, Michael Schotsaert, Thomas Zwaka, Marco Vignuzzi, Kevan M. Shokat, Nevan J. Krogan, Adolfo Garcia-Sastre
Summary: The study revealed that plitidepsin possesses potent antiviral activity against SARS-CoV-2, more effective than the approved drug remdesivir. By inhibiting the eukaryotic translation elongation factor 1A, plitidepsin can significantly reduce viral replication of SARS-CoV-2 in the lungs of mice, making it a promising candidate for COVID-19 treatment.
Review
Biochemistry & Molecular Biology
Birgit T. Priest, Jeff S. McDermott
Article
Chemistry, Medicinal
Bryan H. Norman, Jeff S. McDermott
JOURNAL OF MEDICINAL CHEMISTRY
(2017)
Article
Chemistry, Medicinal
Isaac E. Marx, Thomas A. Dineen, Jessica Able, Christiane Bode, Howard Bregman, Margaret Chu-Moyer, Erin F. DiMauro, Bingfan Du, Robert S. Foti, Robert T. Fremeau, Hua Gao, Hakan Gunaydin, Brian E. Hall, Liyue Huang, Thomas Kornecook, Charles R. Kreiman, Daniel S. La, Joseph Ligutti, Min-Hwa Jasmine Ling, Dong Liu, Jeff S. McDermott, Bryan D. Moyer, Emily A. Peterson, Jonathan T. Roberts, Paul Rose, Jean Wang, Beth D. Youngblood, Violeta Yu, Matthew M. Weiss
ACS MEDICINAL CHEMISTRY LETTERS
(2016)
Article
Pharmacology & Pharmacy
Michaela Kocmalova, Marian Kollarik, Brendan. J. Canning, Fei Ru, R. Adam Herbstsomer, Sonya Meeker, Silvia Fonquerna, Monica Aparici, Montserrat Miralpeix, Xian Xuan Chi, Baolin Li, Ben Wilenkin, Jeff McDermott, Eric Nisenbaum, Jeffrey L. Krajewski, Bradley J. Undem
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2017)
Correction
Chemistry, Medicinal
Isaac E. Marx, Thomas A. Dineen, Jessica Able, Christiane Bode, Howard Bregman, Margaret Chu-Moyer, Erin F. DiMauro, Bingfan Du, Robert S. Foti, Robert T. Fremeau, Hua Gao, Hakan Gunaydin, Brian E. Hall, Liyue Huang, Thomas Kornecook, Charles R. Kreiman, Daniel S. La, Joseph Ligutti, Min-Hwa Jasmine Lin, Dong Liu, Jeff S. McDermott, Bryan D. Moyer, Hanh N. Nguyen, Emily A. Peterson, Jonathan T. Roberts, Paul Rose, Jean Wang, Beth D. Youngblood, Violeta Yu, Matthew M. Weiss
ACS MEDICINAL CHEMISTRY LETTERS
(2017)
Article
Neurosciences
J. M. Witkin, J. L. Smith, X. Ping, S. D. Gleason, M. M. Poe, G. Li, X. Jin, J. Hobbs, J. M. Schkeryantz, J. S. McDermott, A. I. Alatorre, J. N. Siemian, J. W. Cramer, D. C. Airey, K. R. Methuku, V. V. N. P. B. Tiruveedhula, T. M. Jones, J. Crawford, M. J. Krambis, J. L. Fisher, J. M. Cook, R. Cerne
Article
Chemistry, Medicinal
Hanh Nho Nguyen, Howie Bregman, John L. Buchanan, Bingfan Du, Elma Feric, Liyue Huang, Xingwen Li, Joseph Ligutti, Dong Liu, Annika B. Malmberg, David J. Matson, Jeff S. McDermott, Vinod F. Patel, Ben Wilenkin, Anruo Zou, Stefan I. McDonough, Erin F. DiMauro
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2012)
Article
Chemistry, Medicinal
Nagasree Chakka, Howie Bregman, Bingfan Du, Hanh Nho Nguyen, John L. Buchanan, Elma Feric, Joseph Ligutti, Dong Liu, Jeff S. McDermott, Anruo Zou, Stefan I. McDonough, Erin F. DiMauro
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2012)
Article
Neurosciences
Zhi-Yong Tan, Andrew D. Piekarz, Birgit T. Priest, Kelly L. Knopp, Jeffrey L. Krajewski, Jeff S. McDermott, Eric S. Nisenbaum, Theodore R. Cummins
JOURNAL OF NEUROSCIENCE
(2014)
Article
Multidisciplinary Sciences
David J. Matson, Darryl T. Hamamoto, Howard Bregman, Melanie Cooke, Erin F. DiMauro, Liyue Huang, Danielle Johnson, Xingwen Li, Jeff McDermott, Carrie Morgan, Ben Wilenkin, Annika B. Malmberg, Stefan I. McDonough, Donald A. Simone
Article
Neurosciences
Bin Wui, Jeff S. McDermott, Jeffrey L. Krajewski, Kelly L. Knopp, Eric S. Nisenbaum, Theodore R. Cummins, Zhi-Yong Tan
Article
Gastroenterology & Hepatology
Fei Ru, Nikoleta Pavelkova, Jeffrey L. Krajewski, Jeff S. McDermott, Bradley J. Undem, Marian Kollarik
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
(2020)
Article
Pharmacology & Pharmacy
Li Yu, Kojun Tsuji, Izumi Ujihara, Qi Liu, Nikoleta Pavelkova, Takanori Tsujimura, Makoto Inoue, Sonya Meeker, Eric Nisenbaum, Jeff S. McDermott, Jeff Krajewski, Bradley J. Undem, Marian Kollarik, Brendan J. Canning
Summary: The study suggests that the NaV 1.7 channel plays a role in regulating cough and is a potential therapeutic target, but systemic administration of NaV 1.7 inhibitors may lead to side effects such as hypotension and respiratory depression. Topical application of NaV 1.7 inhibitors showed promising antitussive effects, indicating a possible alternative therapeutic strategy to minimize systemic side effects.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Muriel Eaton, Zhefu Que, Jingliang Zhang, Kaethe Beck, Riyi Shi, Jeff McDermott, Michael Ladisch, Yang Yang
Summary: Research findings suggest that citrate salt and citrate mannitol buffer systems lead to increased firing activity of DRG sensory neurons, unlike histidine or saline buffer systems at the same pH level. Lowering the concentration of citrate results in decreased firing intensity of DRG sensory neurons. This highlights the potential nociceptive effects of clinically relevant buffer components used in injectable biologics.
PHARMACEUTICAL RESEARCH
(2021)
Article
Chemistry, Medicinal
Daniel S. La, Emily A. Peterson, Christiane Bode, Alessandro A. Boezio, Howard Bregman, Margaret Y. Chu-Moyer, James Coats, Erin F. DiMauro, Thomas A. Dineen, Bingfan Du, Hua Gao, Russell Graceffa, Hakan Gunaydin, Angel Guzman-Perez, Robert Fremeau, Xin Huang, Christopher Ilch, Thomas J. Kornecook, Charles Kreiman, Joseph Ligutti, Min-Hwa Jasmine Lin, Jeff S. McDermott, Isaac Marx, David J. Matson, Stefan I. McDonough, Bryan D. Moyer, Hanh Nho Nguyen, Kristin Taborn, Violeta Yu, Matthew M. Weiss
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2017)