Article
Immunology
C. Joaquin Caceres, Yanmei Hu, Stivalis Cardenas-Garcia, Xiangmeng Wu, Haozhou Tan, Silvia Carnaccini, L. Claire Gay, Ginger Geiger, Chunlong Ma, Qing-Yu Zhang, Daniela Rajao, Daniel R. Perez, Jun Wang
Summary: The development of a novel deuterium-containing M2-S31N inhibitor UAWJ280 showed broad-spectrum antiviral activity against various influenza A strains and exhibited synergistic effects when combined with oseltamivir in cell culture. In vivo studies on mice demonstrated favorable pharmacokinetic properties and efficacy in improving clinical signs and survival in lethal challenges with oseltamivir-sensitive and -resistant IAV strains.
EMERGING MICROBES & INFECTIONS
(2021)
Article
Chemistry, Multidisciplinary
Anna K. Wright, Joana Paulino, Timothy A. Cross
Summary: This report investigates the structure of the S31N M2 protein from Influenza A virus in the presence of a high molar ratio of lipid. It shows that a high lipid to protein ratio stabilizes a 4-fold-symmetric conformation of the M2 membrane protein. The study highlights the importance of both the character and abundance of the emulated membrane environment for achieving the native protein structure.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Analytical
Julia A. Townsend, Henry M. Sanders, Amber D. Rolland, Chad K. Park, Nancy C. Horton, James S. Prell, Jun Wang, Michael T. Marty
Summary: This study uncovers a wider range of oligomeric complexes of AM2 than previously thought, influenced by the local chemical environment and lipids, providing new insights into potential mechanisms of influenza pathology and pharmacology.
ANALYTICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Changyong Deng, Xiaobo Wang, Tangle Wang, Wei Liu, Xiaolan Yuan, Yan Huang, Shuang Cao
Summary: In this study, compound 4 was identified as a promising drug candidate against the drug-resistant influenza virus strain M2-V27A/S31N. Molecular dynamics simulation showed that compound 4 had stability and flexibility when binding to the target protein. The calculated binding free energy was -106.525 kcal/mol. Physicochemical and pharmacokinetic profiles predicted good bioavailability for compound 4.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Medicinal
Dimitrios Kolokouris, Iris E. Kalenderoglou, Antonios Kolocouris
Summary: Molecular dynamics simulations have accurately described the structure and interactions of the influenza A M2 protein in the membrane environment, providing valuable insights for viroporin systems and potential drug targets.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Review
Biochemistry & Molecular Biology
Sphamadla E. Mtambo, Daniel G. Amoako, Anou M. Somboro, Clement Agoni, Monsurat M. Lawal, Nelisiwe S. Gumede, Rene B. Khan, Hezekiel M. Kumalo
Summary: Influenza viruses (IVs) are known causative agents of respiratory infections and global pandemics in humans, primarily due to their high mutation rates and numerous genomic segments leading to antiviral resistance. Current therapeutic options include vaccines and small molecule inhibitors, but there is a need for continuous development of new anti-influenza therapies targeting the M2 channel and neuraminidase. Further research and development are necessary to design novel inhibitors capable of inhibiting resistant strains.
Article
Biophysics
Kelly L. McGuire, Phillip Smit, Daniel H. Ess, Jonathan T. Hill, Roger G. Harrison, David D. Busath
Summary: Copper complexes can block the influenza virus M2 proton channel, reduce cytotoxicity, and zebrafish-embryo toxicity, by forming coordination complexes with histidine in the proton channel. The energetics of binding and rate constants suggest a two-step process, with copper complex binding as the first step and formation of a Cu-histidine coordination complex as the slow step in current blockage. Electrophysiology and DFT studies also demonstrate that the complexes are effective in blocking the G34E amantadine-resistant mutant.
BIOPHYSICAL JOURNAL
(2021)
Review
Biochemistry & Molecular Biology
Elnaz Aledavood, Beatrice Selmi, Carolina Estarellas, Matteo Masetti, F. Javier Luque
Summary: This review focuses on therapeutic treatments for influenza, specifically targeting key viral proteins including the M2 proton channel and neuraminidase. The article highlights the efforts in studying the M2 proton channel and discusses the challenges in developing efficient small molecule inhibitors and dealing with resistant strains.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Jessica L. Thomaston, Marley L. Samways, Athina Konstantinidi, Chunlong Ma, Yanmei Hu, Hannah E. Bruce Macdonald, Jun Wang, Jonathan W. Essex, William F. DeGrado, Antonios Kolocouris
Summary: Studies have shown that there are slight differences in the way (R)- and (S)-rimantadine bind to the M2 WT channel, but this does not affect the drug's efficacy or binding kinetics.
Article
Chemistry, Multidisciplinary
Kumar Tekwani Movellan, Riza Dervisoglu, Stefan Becker, Loren B. Andreas
Summary: The study reveals the presence of a bound water molecule forming a hydrogen bond with the δ1 nitrogen of histidine 37 in the M2 conductance domain.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Virology
Rashid Manzoor, Nao Eguchi, Reiko Yoshida, Hiroichi Ozaki, Tatsunari Kondoh, Kosuke Okuya, Hiroko Miyamoto, Ayato Takada
Summary: Protective immunity against influenza A viruses mainly relies on antibodies to hemagglutinin (HA), but the conserved M2 protein has been studied as a vaccine antigen for cross-protective immunity. This study reveals that an M2-specific antibody can interfere with the HA-M2 association, providing a novel mechanism for the antiviral activity of M2-specific antibodies.
JOURNAL OF VIROLOGY
(2021)
Article
Microbiology
Paulina Koszalka, Ankita George, Vijaykrishna Dhanasekaran, Aeron C. Hurt, Kanta Subbarao
Summary: Combination therapy with influenza drugs baloxavir and oseltamivir can reduce the selection of viruses with reduced drug susceptibility. In animal models, combination therapy and monotherapy have similar effectiveness in reducing viral titers, but combination therapy can decrease the selection of viruses with reduced susceptibility to baloxavir.
Review
Virology
Yaqin Bai, Jeremy C. Jones, Sook-San Wong, Mark Zanin
Summary: Hemagglutinin and neuraminidase are critical parts of influenza viruses, serving as targets for immune response and antiviral drugs. Neuraminidase inhibitors like oseltamivir are commonly used against influenza, while antivirals targeting hemagglutinin are newer with a higher resistance threshold.
Review
Microbiology
Edward C. Holmes, Aeron C. Hurt, Zuzana Dobbie, Barry Clinch, John S. Oxford, Pedro A. Piedra
Summary: Influenza poses a significant burden on society and healthcare systems. Antiviral resistance can lead to uncertainty among prescribers and policy makers. Antiviral treatment generally provides clinical benefit and resistant viruses are usually associated with reduced fitness.
CLINICAL MICROBIOLOGY REVIEWS
(2021)
Article
Chemistry, Organic
Xiaoxia Huang, Yarui Li, Jieyin He, Shiyong Peng, Jian Wang, Ming Lang
Summary: A novel N-heterocyclic carbene (NHC)-catalyzed asymmetric [3 + 3] cycloaddition between alpha-bromoenals and 5-aminoisoxazoles has been developed. Various dihydroisoxazolo[5,4-b]pyridin-6-ones were obtained in high yields (up to 99%) with excellent enantioselectivities (up to >99%) under mild conditions. Notably, this is the first example of direct catalytic asymmetric synthesis of dihydroisoxazolo[5,4-b]pyridin-6-ones.
ORGANIC CHEMISTRY FRONTIERS
(2023)
Article
Chemistry, Medicinal
Naoya Kitamura, Michael Dominic Sacco, Chunlong Ma, Yanmei Hu, Julia Alma Townsend, Xiangzhi Meng, Fushun Zhang, Xiujun Zhang, Mandy Ba, Tommy Szeto, Adis Kukuljac, Michael Thomas Marty, David Schultz, Sara Cherry, Yan Xiang, Yu Chen, Jun Wang
Summary: This study discovered 23R, one of the most potent and selective noncovalent SARS-CoV-2 MPpro inhibitors reported to date, and a novel binding pocket in MPpro that can be explored for inhibitor design.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Jun Wang, Yanmei Hu, Madeleine Zheng
Summary: Enterovirus A71 (EV-A71) is a significant human pathogen that particularly affects children. Existing vaccines for EV-A71 have limited protection and reduced efficacy against emerging strains. No approved antiviral for EV-A71 is currently available. Researchers have made progress in developing antivirals by targeting viral proteins and host factors, although some approaches have shown limited efficacy or side effects.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Virology
Yanmei Hu, Hyunil Jo, William F. DeGrado, Jun Wang
Summary: This study discovered the antiviral mechanism of Brilacidin, which inhibits the entry of multiple human coronaviruses by targeting HSPGs on the host cell surface. The study also found a strong synergistic effect of Brilacidin in combination with remdesivir against a specific coronavirus.
JOURNAL OF MEDICAL VIROLOGY
(2022)
Article
Pharmacology & Pharmacy
Chunlong Ma, Haozhou Tan, Juliana Choza, Yuyin Wang, Jun Wang
Summary: This study systematically characterizes the target specificity of Mpro inhibitors for COVID-19 and highlights the need for stringent hit validation in early-stage drug discovery.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Biochemistry & Molecular Biology
Xu Zhou, Lingxiang Zhu, Cheryl Bondy, Jun Wang, Qianwen Luo, Yin Chen
Summary: Current options for preventing or treating influenza are limited. However, a new study has discovered that a small molecule inhibitor called AG1478 has potent antiviral activity against influenza. The inhibitor targets the Golgi-specific GBF1-ARF1 system, rather than the EGFR inhibitory activity or interferon. This discovery highlights the potential of targeting host factors like GBF1 for developing effective treatments against influenza.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Haozhou Tan, Yanmei Hu, Prakash Jadhav, Bin Tan, Jun Wang
Summary: This article summarizes the significant progress in structure-based design and high-throughput screening of SARS-CoV-2 papain-like protease (PLpro) inhibitors since the beginning of the pandemic. Encouraging achievements include the development of non-covalent and covalent inhibitors with favorable pharmacokinetic properties. The article also identifies knowledge gaps that need to be addressed to advance PLpro inhibitors to clinical application.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Haozhou Tan, Chunlong Ma, Jun Wang
Summary: The COVID-19 pandemic has led to a significant interest in antiviral drug discovery. Recent studies have identified two natural compounds, dieckol and PGG, as potential SARS-CoV-2 M-pro inhibitors. However, further research has shown that neither compound inhibits M-pro, but PGG does inhibit SARS-CoV-2 PLpro. Unfortunately, PGG also exhibits cytotoxicity. Additionally, other compounds previously reported as SARS-CoV-2 PLpro inhibitors were found to be ineffective.
MEDICINAL CHEMISTRY RESEARCH
(2022)
Article
Chemistry, Medicinal
Chunlong Ma, Yanmei Hu, Yuyin Wang, Juliana Choza, Jun Wang
Summary: The global COVID-19 pandemic has highlighted the urgent need for effective antiviral drugs. This study focused on the development of inhibitors for the papain-like protease (PLpro), an important drug target due to its role in viral replication and host immune response. By screening a bioactive compound library, three compounds (EACC, KY-226, and tropifexor) were identified as potent PLpro inhibitors. Tropifexor, in particular, showed antiviral activity against SARS-CoV-2 in cells without causing cytotoxicity. These findings suggest that tropifexor has the potential to be further developed as an antiviral drug against SARS-CoV-2.
ACS INFECTIOUS DISEASES
(2022)
Article
Biochemistry & Molecular Biology
Kimberly Gomez, Cheng Tang, Bin Tan, Samantha Perez-Miller, Dongzhi Ran, Santiago Loya, Aida Calderon-Rivera, Harrison J. Stratton, Paz Duran, Kyleigh A. Masterson, Anna T. Gabrielsen, Omar Alsbiei, Angie Dorame, Maria Serafini, Aubin Moutal, Jun Wang, Rajesh Khanna
Summary: In this study, a library of compounds that inhibit T-type calcium channels was synthesized and screened, leading to the discovery of a novel blocker with in vivo efficacy against various types of pain.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Multidisciplinary Sciences
Michael D. Sacco, Shaohui Wang, Swamy R. Adapa, Xiujun Zhang, Eric M. Lewandowski, Maura Gongora, Dimitra Keramisanou, Zachary D. Atlas, Julia A. Townsend, Jean R. Gatdula, Ryan T. Morgan, Lauren R. Hammond, Michael T. Marty, Jun Wang, Prahathees J. Eswara, Ioannis Gelis, Rays H. Y. Jiang, Xingmin Sun, Yu Chen
Summary: β-lactam antibiotics inhibit bacterial cell wall synthesis by targeting PBPs. This study reveals the unique structural features of PBPs in C. difficile and sheds light on the mechanisms underlying beta-lactam resistance in this pathogen, providing new insights for the treatment of Clostridioides difficile infection.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Jun Wang, Md Shahed-AI-Mahmud, Angelo Chen, Kan Li, Haozhou Tan, Ryan Joyce
Summary: The current monkeypox outbreaks during the COVID-19 pandemic have sparked renewed interest in antiviral drugs for orthopoxviruses. This perspective aims to summarize the antiviral activity, mechanism of action, and resistance mechanisms of orthopoxvirus antivirals to facilitate the development of additional drugs. The goal is to provide insights for medicinal chemists to prioritize drug targets and candidates for further development, thereby speeding up the discovery of orthopoxvirus antiviral drugs.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Virology
Joshua Frost, Michael J. Rudy, J. Smith Leser, Haozhou Tan, Yanmei Hu, Jun Wang, Penny Clarke, Kenneth L. Tyler
Summary: Recent outbreaks of EV-D68 in 2014, 2016, and 2018 have led to over 600 cases of a paralytic illness called AFM. AFM primarily affects children, lacks an FDA-approved treatment, and shows limited recovery from limb weakness in many patients.
JOURNAL OF VIROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Noah H. Somberg, Joao Medeiros-Silva, Hyunil Jo, Jun Wang, William F. Degrado, Mei Hong
Summary: This study used solid-state NMR to measure the binding distance between 5-(N,N-hexamethylene) amiloride (HMA) and the envelope protein (E) of SARS-CoV-2. The results showed that HMA binds to E with a stoichiometry of one drug per pentamer and is located on the lipid-facing surface of the protein. These findings provide insights into the inhibition mechanism of HMA for SARS-CoV-2 E.
Meeting Abstract
Biophysics
Ankan Nath, Soohyun Lee, Trivikram R. Molugu, Jun Wang, Andrey V. Struts, Michael F. Brown
BIOPHYSICAL JOURNAL
(2022)
Article
Chemistry, Medicinal
Chunlong Ma, Jun Wang
Summary: The study aimed to validate a range of compounds as SARS-CoV-2 PLpro inhibitors, but results showed that these compounds did not exhibit effective inhibition of PLpro at both enzymatic and cellular levels. Therefore, further efforts are needed to search for more potent and specific SARS-CoV-2 PLpro inhibitors.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2022)