Article
Biochemistry & Molecular Biology
Ruyu Wang, Qing Hu, Haonan Wang, Guanghao Zhu, Mengge Wang, Qian Zhang, Yishu Zhao, Chunyu Li, Yani Zhang, Guangbo Ge, Hongzhuan Chen, Lili Chen
Summary: Vitamin K3 was found to have potent inhibitory activity against SARS-CoV-2 3CL(pro) and could form a covalent bond with it, while 5,8-dihydroxy-1,4-naphthoquinone showed even higher inhibitory activity. These findings provide valuable information for the development of novel inhibitors against SARS-CoV-2.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Biochemistry & Molecular Biology
Yuan Xiong, Guang-Hao Zhu, Ya-Ni Zhang, Qing Hu, Hao-Nan Wang, Hao-Nan Yu, Xiao-Ya Qin, Xiao-Qing Guan, Yan-Wei Xiang, Hui Tang, Guang-Bo Ge
Summary: The study demonstrated that flavonoids in Ampelopsis grossedentata extract strongly and time-dependently inhibit SARS-CoV-2 3C-like protease. Flavonoids such as myricetin and dihydromyricetin were identified as key constituents with significant inhibitory effects on SARS-CoV-2 3C-like protease.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Review
Chemistry, Medicinal
Jiajie Zhu, Haiyan Zhang, Qinghong Lin, Jingting Lyu, Lu Lu, Hanxi Chen, Xuning Zhang, Yanjun Zhang, Keda Chen
Summary: This paper discusses the progress of peptidomimetic inhibitors targeting SARS-CoV-2 3CLpro and briefly discusses the effects of small-molecule compounds with antiviral and anti-inflammatory properties on 3CLpro.
DRUG DESIGN DEVELOPMENT AND THERAPY
(2022)
Article
Chemistry, Medicinal
Julia K. K. Stille, Jevgenijs Tjutrins, Guanyu Wang, Felipe A. A. Venegas, Christopher Hennecker, Andres M. Rueda, Itai Sharon, Nicole Blaine, Caitlin E. Miron, Sharon Pinus, Anne Labarre, Jessica Plescia, Mihai Burai Patrascu, Xiaocong Zhang, Alexander S. Wahba, Danielle Vlaho, Mitchell J. Huot, T. Martin Schmeing, Anthony K. K. Mittermaier, Nicolas Moitessier
Summary: Severe diseases like COVID-19, SARS, and MERS highlight the urgent need for antiviral drugs. The development of inhibitors targeting 3CL(pro) is promising in combating these deadly viruses. Researchers have made efforts to design and synthesize covalent inhibitors to suppress the activity of viral protease.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Plant Sciences
Ya-Ni Zhang, Guang-Hao Zhu, Wei Liu, Yuan Xiong, Qing Hu, Xiao-Yu Zhuang, Gui-Hua Jia, Wei-Dong Zhang, Guang-Bo Ge
Summary: The study aims to discover new covalent inhibitors against SARS-CoV-2 3CLpro from herbal medicines. Ginkgo biloba extract 50 (GBE50) was found to effectively inhibit the activity of SARS-CoV-2 3CLpro, and the key constituents in GBE50 were identified. A total of 38 constituents and 26 peptides modified by 18 constituents were identified in GBE50. Gallocatechin and sciadopitysin showed the strongest inhibitory activity.
Article
Chemistry, Organic
Manashjyoti Konwar, Diganta Sarma
Summary: COVID-19, caused by SARS-CoV-2, has infected over 29 million people worldwide with a high mortality rate. Research shows that a chymotripsin-like cystein protease (3CL(pro)) is crucial for the virus replication, and developing inhibitors for this enzyme could be a promising approach to combat the pandemic.
Article
Biochemistry & Molecular Biology
Mubarak A. Alamri, Muhammad Tahir ul Qamar, Muhammad Usman Mirza, Rajendra Bhadane, Safar M. Alqahtani, Iqra Muneer, Matheus Froeyen, Outi M. H. Salo-Ahen
Summary: The study identifies potential covalent inhibitors through a structure-based approach and repurposes FDA-approved drugs against SARS-CoV-2 3CLpro. Molecular dynamics simulations characterize the binding mechanism and dynamic stability between the compounds and the protease. Identified compounds show promise as potential inhibitors for further development as COVID-19 drugs, including FDA-approved anti-hepatitis-C virus drugs paritaprevir and simeprevir.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2021)
Article
Chemistry, Medicinal
Kuojun Zhang, Tianyu Wang, Maotian Li, Mu Liu, He Tang, Lin Wang, Ke Ye, Jiamei Yang, Sheng Jiang, Yibei Xiao, Youhua Xie, Meiling Lu, Xiangyu Zhang
Summary: Using medicinal chemistry and rational drug design strategies, we identified a series of nonpeptidic, noncovalent SARS-CoV-2 Mpro inhibitors based on baicalein. Compound C7 showed superior inhibitory activity against SARS-CoV-2 Mpro and improved physicochemical and drug metabolism and pharmacokinetics (DMPK) properties compared to baicalein. It also exhibited stronger antiviral activity against SARS-CoV-2 replication in Vero E6 cells with low cytotoxicity. These findings suggest that C7 is a promising lead compound for the development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Seri Jo, Luca Signorile, Suwon Kim, Mi-Sun Kim, Oscar Huertas, Raul Insa, Nuria Reig, Dong Hae Shin
Summary: In this study, researchers identified three compounds through drug repurposing that showed strong inhibitory activity against the main protease of the novel coronavirus. One of these compounds demonstrated potential antiviral activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Subramanyam Vankadara, Yun Xuan Wong, Boping Liu, Yi Yang See, Li Hong Tan, Qian Wen Tan, Gang Wang, Ratna Karuna, Xue Guo, Shu Ting Tan, Jia Yi Fong, Joma Joy, C. S. Brian Chia
Summary: The COVID-19 pandemic has highlighted the urgent need for more antiviral drugs, with research focusing on peptidomimetic 3CLpro inhibitors as potential therapeutics. A head-to-head comparison of fifteen reported inhibitors in a standard assay was conducted to identify potent candidates for development, while also discussing inhibitor design and suitable warheads.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Jenny Desantis, Beatrice Mercorelli, Marta Celegato, Federico Croci, Alessandro Bazzacco, Massimo Baroni, Lydia Siragusa, Gabriele Cruciani, Arianna Loregian, Laura Goracci
Summary: Indomethacin (INM) has shown antiviral activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in drug repurposing studies. Recent research indicates that the antiviral activity of INM could be attributed to its inhibition of human prostaglandin E synthase type 2 (PGES-2). This study explores the application of Proteolysis Targeting Chimeras (PROTACs) technology to develop more potent INM-derived PROTACs with anti-CoV activity, which showed a strong improvement in antiviral potency compared to INM. Molecular modelling studies suggest that human PGES-2 is a potential target of INM-based antiviral PROTACs, paving the way for the development of host-directed anti-coronavirus strategies.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Barbara Herlah, Andrej Hoivik, Luka Jamsek, Katja Valjavec, Norio Yamamoto, Tyuji Hoshino, Kristof Kranjc, Andrej Perdih
Summary: The rapid development of novel antiviral drugs is crucial in combating the global COVID-19 pandemic caused by SARS-CoV-2. Drug repurposing and the development of new molecules have shown promising candidates. This study focuses on the design and synthesis of versatile molecular scaffolds with high functionalization capabilities to inhibit the main protease of SARS-CoV-2. Inhibition assays identified compounds that can effectively inhibit the protease, with the most promising compound showing potential for further optimization. Molecular simulations and calculations provide additional insights for future development.
Article
Biochemistry & Molecular Biology
Kansate Prasertsuk, Kasidit Prongfa, Piyapach Suttiwanich, Nathaphat Harnkit, Mattanun Sangkhawasi, Pongsakorn Promta, Pramote Chumnanpuen
Summary: To control the COVID-19 pandemic, it is urgent to develop antivirals that target the SARS-CoV-2 virus. This study used computer-aided screening to identify potential antiviral peptides from hemp seed. These peptides demonstrated stability and the ability to inhibit the viral life cycle, suggesting their potential as alternative therapeutics against COVID-19.
Article
Chemistry, Medicinal
Fu-Mao Zhang, Ting Huang, Feng Wang, Gui-Shan Zhang, Donglan Liu, Jun Dai, Jian-Wei Zhang, Qing-Hua Li, Guo-Qiang Lin, Dingding Gao, Jincun Zhao, Ping Tian
Summary: COVID-19 remains a significant threat to human health and effective drugs are needed. Compound D6 shows strong inhibitory activity against SARS-CoV-2 3CLpro and has favorable selectivity towards host proteases. The investigation of the 2-sulfoxyl-1,3,4-oxadiazole scaffold provides valuable insights for the design of potent covalent 3CLpro inhibitors for COVID-19 treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Virology
Jonathan M. O. Rawson, Alice Duchon, Olga A. Nikolaitchik, Vinay K. Pathak, Wei-Shau Hu
Summary: A novel cell-based luciferase complementation reporter assay has been developed to identify inhibitors of SARS-CoV-2 3CL(pro) in a BSL-2 setting. This assay can easily distinguish true 3CL(pro) inhibition from cytotoxicity, reducing false positives during screening and facilitating the identification of more potent inhibitors.
Article
Multidisciplinary Sciences
Shin-ichiro Hattori, Nobuyo Higashi-Kuwata, Hironori Hayashi, Srinivasa Rao Allu, Jakka Raghavaiah, Haydar Bulut, Debananda Das, Brandon J. Anson, Emma K. Lendy, Yuki Takamatsu, Nobutoki Takamune, Naoki Kishimoto, Kazutaka Murayama, Kazuya Hasegawa, Mi Li, David A. Davis, Eiichi N. Kodama, Robert Yarchoan, Alexander Wlodawer, Shogo Misumi, Andrew D. Mesecar, Arun K. Ghosh, Hiroaki Mitsuya
Summary: In this study, two small-molecule compounds, GRL-1720 and 5h, are characterized for their anti-SARS-CoV-2 properties targeting the virus main protease (M-pro). These compounds showed synergistic antiviral effects when combined with remdesivir in vitro, indicating their potential as lead inhibitors for the development of therapeutics against SARS-CoV-2 infection.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Arun K. Ghosh, Satish Kovela, Ashish Sharma, Dana Shahabi, Ajay K. Ghosh, Denver R. Hopkins, Monika Yadav, Megan E. Johnson, Johnson Agniswamy, Yuan-Fang Wang, Shin-Ichiro Hattori, Nobuyo Higashi-Kuwata, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya
Summary: This study reports the design, synthesis, X-ray structural analysis, and biological evaluation of highly potent HIV-1 protease inhibitors. The inhibitors combine a novel cyclohexane-fused tricyclic bis-tetrahydrofuran as P2 ligands with various P1 and P2' ligands. The inhibitor with difluoromethylphenyl P1 ligand and cyclopropylaminobenzothiazole P2' ligand demonstrates the most potent antiviral activity, including against highly multidrug-resistant HIV-1 variants. Two high-resolution X-ray structures of inhibitor-bound HIV-1 protease provide molecular insight.
Article
Multidisciplinary Sciences
Britton Boras, Rhys M. Jones, Brandon J. Anson, Dan Arenson, Lisa Aschenbrenner, Malina A. Bakowski, Nathan Beutler, Joseph Binder, Emily Chen, Heather Eng, Holly Hammond, Jennifer Hammond, Robert E. Haupt, Robert Hoffman, Eugene P. Kadar, Rob Kania, Emi Kimoto, Melanie G. Kirkpatrick, Lorraine Lanyon, Emma K. Lendy, Jonathan R. Lillis, James Logue, Suman A. Luthra, Chunlong Ma, Stephen W. Mason, Marisa E. McGrath, Stephen Noell, R. Scott Obach, Matthew N. O' Brien, Rebecca O'Connor, Kevin Ogilvie, Dafydd Owen, Martin Pettersson, Matthew R. Reese, Thomas F. Rogers, Romel Rosales, Michelle I. Rossulek, Jean G. Sathish, Norimitsu Shirai, Claire Steppan, Martyn Ticehurst, Lawrence W. Updyke, Stuart Weston, Yuao Zhu, Kris M. White, Adolfo Garcia-Sastre, Jun Wang, Arnab K. Chatterjee, Andrew D. Mesecar, Matthew B. Frieman, Annaliesa S. Anderson, Charlotte Allerton
Summary: Researchers found that PF-07304814 exhibits broad-spectrum activity in inhibiting SARS-CoV and SARS-CoV-2, supported by its ADME and safety profile for clinical development. The 3CL protease, crucial in various coronaviruses, is effectively inhibited by PF-00835231 as a single agent, and shows even better results in combination with remdesivir.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Multidisciplinary
Arun K. Ghosh, Amartyo J. Basu, Che-Sheng Hsu, Monika Yadav
Summary: The asymmetric 1,2-carbamoyl rearrangement reaction investigated in this study shows potential applications in obtaining α-hydroxy amide derivatives with excellent diastereoselectivity and high yield.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Infectious Diseases
Nobumasa Okumura, Shinya Tsuzuki, Sho Saito, Shin-ichiro Hattori, Junko S. Takeuchi, Tomoya Saito, Mugen Ujiie, Masayuki Hojo, Noriko Iwamoto, Wataru Sugiura, Hiroaki Mitsuya, Norio Ohmagari
Summary: The Omicron variant with multiple amino acid mutations in its spike proteins may evade immunity from vaccination, and two doses of vaccination may not provide sufficient neutralizing activity against the Omicron variant.
JOURNAL OF INFECTION AND CHEMOTHERAPY
(2022)
Article
Parasitology
Nunya Chotiwan, Carlos A. Brito-Sierra, Gabriella Ramirez, Elena Lian, Jeffrey M. Grabowski, Babara Graham, Catherine A. Hill, Rushika Perera
Summary: This study identified several fatty acid synthase genes in Aedes aegypti mosquitoes and found that AaFAS1 is the predominant type in adult mosquitoes. This gene is highly expressed in adult females and facilitates the replication and transmission of dengue viruses.
PARASITES & VECTORS
(2022)
Article
Chemistry, Medicinal
Arun K. Ghosh, Hao Yuan
Summary: This study focuses on the enantioselective syntheses and structural analysis of cytotoxic agents from marine dinoflagellates. The correct structures of the compounds were assigned through detailed analysis of spectral data. However, the synthetic compounds did not exhibit significant cytotoxic properties in preliminary biological evaluation.
Article
Multidisciplinary Sciences
Lauren E. Williamson, Abhishek Bandyopadhyay, Kevin Bailey, Devika Sirohi, Thomas Klose, Justin G. Julander, Richard J. Kuhn, James E. Crowe
Summary: This report presents cryo-electron microscopy reconstructions of three neutralizing human monoclonal antibodies against Eastern equine encephalitis virus (EEEV), and analyzes the factors contributing to the differences in their neutralization potencies. Structural and biophysical insights are provided, which can inform the design of candidate vaccines and therapeutic antibodies for all icosahedral viruses.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Chemistry, Medicinal
Arun K. Ghosh, Dana Shahabi, Mackenzie E. C. Imhoff, Satish Kovela, Ashish Sharma, Shin-ichiro Hattori, Nobuyo Higashi-Kuwata, Hiroaki Mitsuya, Andrew D. Mesecar
Summary: This study reports the synthesis and biological evaluation of a series of small molecule SARS-CoV-2 PLpro inhibitors. By comparing the activity of selected compounds in SARS-CoV-1 and SARS-CoV-2, it was found that replacing the carboxamide functionality with sulfonamide derivatives resulted in potent PLpro inhibitors with antiviral activity.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Multidisciplinary Sciences
Manabu Aoki, Hiromi Aoki-Ogata, Haydar Bulut, Hironori Hayashi, Nobutoki Takamune, Naoki Kishimoto, Hiroki Tanaka, Nobuyo Higashi-Kuwata, Shin-ichiro Hattori, Debananda Das, Kalapala Venkateswara Rao, Kazuya Iwama, David A. Davis, Kazuya Hasegawa, Kazutaka Murayama, Robert Yarchoan, Arun K. Ghosh, Alice K. Pau, Shinichi Machida, Shogo Misumi, Hiroaki Mitsuya
Summary: This study found that a multidrug-resistant HIV-1 variant HIVKGD is highly susceptible to a HIV-1 protease inhibitor GRL-142, which disrupts the nuclear import of the virus. The highly INSTI-resistant HIV-1 variants were also sensitive to GRL-142, indicating that NLS-targeting agents may serve as salvage therapy for INSTI-resistant individuals.
Article
Chemistry, Organic
Arun K. Ghosh, Monika Yadav
Summary: Nirmatrelvir (Paxlovid) is an FDA approved drug that targets SARS-COV-2 3CLprotease. An optically active synthesis of nirmatrelvir was developed to avoid epimerization, which is a crucial step in the synthesis process. A ZnCl2-mediated direct N-trifluroacetylation method was utilized to overcome the epimerization problem and successfully synthesize nirmatrelvir derivatives without significant epimerization.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)