Article
Immunology
Hongxia Yan, Tong Wu, Yue Chen, Hongliang Jin, Li Li, Yuanmei Zhu, Huihui Chong, Yuxian He
Summary: A bifunctional inhibitor, 2P23-iMab, was designed in this study by genetically conjugating a potent HIV fusion inhibitor, 2P23, to the scFv of ibalizumab. This new inhibitor showed significantly improved inhibitory activity against a broad panel of HIV-1 pseudoviruses and displayed potent activity against viruses resistant to iMab, T-20, or 2P23. The study provides insights into the development of novel bispecific HIV entry inhibitors with potent and broad-spectrum antiviral activity.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Yunjiang Zhou, Yunting Zou, Mei Yang, Shuang Mei, Xiaohao Liu, Huiyun Han, Chang-Dong Zhang, Miao-Miao Niu
Summary: This study demonstrates that a cyclic D-peptide NKTP-3, targeting both NRP1 and KRAS(G12D), could be a potential chemotherapeutic agent for KRAS(G12D)-driven lung cancer treatment.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Medicinal
Ruifang Jia, Jian Zhang, Chiara Bertagnin, Srinivasulu Cherukupalli, Wei Ai, Xiao Ding, Zhuo Li, Jiwei Zhang, Han Ju, Xiuli Ma, Arianna Loregian, Bing Huang, Peng Zhan, Xinyong Liu
Summary: The structural modifications at the 150-cavity of influenza virus neuraminidases can result in more potent oseltamivir derivatives, with compound 5c showing the most promising activity. In vitro and in vivo studies demonstrated low cytotoxicity and no acute toxicity of 5c, indicating its potential as a drug candidate.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Olaia Marti-Mari, Belen Martinez-Gualda, Irene Fernandez-Barahona, Alberto Mills, Rana Abdelnabi, Sam Noppen, Johan Neyts, Dominique Schols, Maria-Jose Camarasa, Fernando Herranz, Federico Gago, Ana San-Felix
Summary: Recently, we have discovered a novel family of compounds that are smaller in size and possess dual anti-HIV and anti-EV71 activities. Some of the derivatives showed greater potency and selectivity against HIV-1, HIV-2, and EV-A71 compared to the prototype compound AL-470. A fluorescent probe exhibited specific tropism for the intestines and lungs, which are important niches for the human microbiome in health and disease.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Cell Biology
Carl J. Balibar, Daniel J. Klein, Beata Zamlynny, Tracy L. Diamond, Zhiyu Fang, Carol A. Cheney, Jan Kristoff, Meiqing Lu, Marina Bukhtiyarova, Yangsi Ou, Min Xu, Lei Ba, Steven S. Carroll, Abdellatif El Marrouni, John F. Fay, Ashley Forster, Shih Lin Goh, Meigang Gu, Daniel Krosky, Daniel I. S. Rosenbloom, Payal Sheth, Deping Wang, Guoxin Wu, Matthias Zebisch, Tian Zhao, Paul Zuck, Jay Grobler, Daria J. Hazuda, Bonnie J. Howell, Antonella Converso
Summary: Antiretroviral therapy can inhibit HIV-1 replication but cannot cure the infection due to the persistence of a reservoir in the host genome. Reduction of this reservoir is important for HIV-1 cure. Some nonnucleoside reverse transcriptase inhibitors have shown selective cytotoxicity against HIV-1 in vitro, but their concentrations required are much higher than approved dosages. By focusing on this secondary activity, researchers have discovered bifunctional compounds called targeted activators of cell kill (TACK) that can kill HIV-1-infected cells at clinically achievable concentrations. These TACK molecules bind to the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators, promoting dimerization and premature intracellular viral protease activation, leading to death of HIV-1(+) cells. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4(+) T cells, providing a potential immune-independent clearance strategy.
SCIENCE TRANSLATIONAL MEDICINE
(2023)
Article
Chemistry, Medicinal
Lutete Peguy Khonde, Rudolf Mueller, Grant A. Boyle, Virsinha Reddy, Aloysius T. Nchinda, Charles J. Eyermann, Stephen Fienberg, Vinayak Singh, Alissa Myrick, Efrem Abay, Mathew Njoroge, Nina Lawrence, Qin Su, Timothy G. Myers, Helena I. M. Boshoff, Clifton E. Barry, Frederick A. Sirgel, Paul D. van Helden, Lisa M. Massoudi, Gregory T. Robertson, Anne J. Lenaerts, Gregory S. Basarab, Sandeep R. Ghorpade, Kelly Chibale
Summary: A study identified a moderately active compound against Mycobacterium tuberculosis through high-throughput screening, with potential bactericidal activity and retention of activity against drug-resistant strains. Initial investigations suggested inhibition of cell wall biosynthesis as a possible mode of action, but the specific mechanism remains unclear.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Songyi Xue, Wei Xu, Lei Wang, Ling Xu, Laurent Calcul, Peng Teng, Lu Lu, Shibo Jiang, Jianfeng Cai
Summary: The HIV-1 epidemic has significant social and economic implications for public health, and the development of new antivirus drugs is urgently needed. Researchers have found that sulfonyl-α-AApeptides show potential as anti-HIV-1 agents by mimicking certain proteins involved in HIV fusion. These peptides were able to control HIV-1 infection and could potentially be used to treat infections within the central nervous system. This design strategy may also have applications in modulating other protein-protein interactions.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Siew Pheng Lim
Summary: Despite the availability of vaccines and therapeutics, continuous genetic alterations in the SARS-CoV-2 virus pose a persistent threat, especially to immunocompromised and elderly individuals. The virus enters host cells via the interaction of its spike protein (S protein) with different receptors on the cell surface, such as angiotensin-converting enzyme 2 (ACE2). This review discusses therapeutic approaches to block the interaction between SARS-CoV-2 and host cell receptors, as well as the identification of auxiliary entry receptors.
ANTIVIRAL RESEARCH
(2023)
Article
Medicine, General & Internal
Zhongli Liu, Xiaola Guo, Aijiang Guo, Shengying Zhang, Yang Zou, Yugui Wang, Xiaolu Li, Wei He, Lixia Pu, Shaohua Zhang, Qiaoying Zeng, Xuepeng Cai, Shuai Wang
Summary: This study identifies nelfinavir as the most effective drug against echinococcosis and elucidates its mechanism of action on the parasite. Through comparison of drug efficacy, this research provides valuable insights into the development of single-drug therapy for co-infection between HIV and helminth diseases.
Article
Chemistry, Medicinal
Eric P. Gillis, Kyle Parcella, Michael Bowsher, James H. Cook, Christiana Iwuagwu, B. Narasimhulu Naidu, Manoj Patel, Kevin Peese, Haichang Huang, Lourdes Valera, Chunfu Wang, Kasia Kieltyka, Dawn D. Parker, Jean Simmermacher, Eric Arnoult, Robert T. Nolte, Liping Wang, John A. Bender, David B. Frennesson, Mark Saulnier, Alan Xiangdong Wang, Nicholas A. Meanwell, Makonen Belema, Umesh Hanumegowda, Susan Jenkins, Mark Krystal, John F. Kadow, Mark Cockett, Robert Fridell
Summary: Long-acting HIV-1 antiretroviral therapy offers advantages over daily oral therapy, but the criteria for compounds entering clinical development are high. This study reports the discovery of capsid inhibitors with a quinazolinone core that maintain potent activity against HIV-1 infection while tolerating structural modifications. The characterization of a prototypical compound, GSK878, including X-ray co-crystal structure and pharmacokinetic data in animals, is presented.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Bingchen Yu, Shanshan Li, Takako Tabata, Nanxi Wang, Li Cao, G. Renuka Kumar, Wei Sun, Jun Liu, Melanie Ott, Lei Wang
Summary: This study developed covalent nanobodies that bind irreversibly with SARS-CoV-2, increasing neutralization potency against wild-type virus and its variants. These insights into increased potency can be valuable for developing effective therapeutics against viral infections.
Article
Chemistry, Medicinal
Natalie Losada, Francesc X. Ruiz, Francesca Curreli, Kevin Gruber, Alyssa Pilch, Kalyan Das, Asim K. Debnath, Eddy Arnold
Summary: This study focuses on compounds (NBD derivatives) originally developed to bind to HIV-1 gp120, some of which inhibit RT. Crystal structures of three NBD compounds in complex with HIV-1 RT have been determined, correlating with RT enzyme inhibition and antiviral activity, to develop structure-activity relationships. Two lead compounds, NBD-14189 and NBD-14270, show potent antiviral activity and low cytotoxicity.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Michael B. Plewe, Vidyasagar Reddy Gantla, Nadezda Sokolova, Young-Jun Shin, Shibani Naik, Eric R. Brown, Alexandra Fetsko, Lihong Zhang, Birte Kalveram, Alexander N. Freiberg, Greg Henkel, Ken McCormack
Summary: The study identified a novel heterocyclic chemical series with potent activity against both Old and New World arenaviruses, showing attractive metabolic stability and lack of hERG K+ channel or CYP enzyme inhibition. Optimized lead compounds could provide a cost-effective broad-spectrum arenavirus therapeutic to help minimize treatment costs for emerging viruses in economically challenged geographical settings.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Yonggang Meng, Bin Yu, He Huang, Youmei Peng, Ertong Li, Yongfang Yao, Chuanjun Song, Wenquan Yu, Kaikai Zhu, Kai Wang, Dongxu Yi, Jinfa Du, Junbiao Chang
Summary: Osimertinib is a standard therapy for advanced EGFR mutation-positive NSCLC, but its toxic metabolite AZ5104 has caused unwanted toxicities. Through structural optimization, dosimertinib was discovered as a highly potent, selective, and less toxic clinical candidate for EGFR-targeted therapy, showing promising preclinical efficacy.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Microbiology
Masayuki Amano, Ravikiran S. Yedidi, Pedro Miguel Salcedo-Gomez, Hironori Hayashi, Kazuya Hasegawa, Cuthbert D. Martyr, Arun K. Ghosh, Hiroaki Mitsuya
Summary: Two newly developed CNS-targeting HIV-1 protease inhibitors, GRL-08513 and GRL-08613, showed potent inhibition against multiple drug-resistant HIV-1 variants and favorable blood-brain barrier penetration.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Biochemistry & Molecular Biology
Bo Zhao, Shutong Xu, Xianchi Dong, Chafen Lu, Timothy A. Springer
JOURNAL OF BIOLOGICAL CHEMISTRY
(2018)
Article
Multidisciplinary Sciences
Xianchi Dong, Bo Zhao, Roxana E. Iacob, Jianghai Zhu, Adem C. Koksal, Chafen Lu, John R. Engen, Timothy A. Springer
Article
Multidisciplinary Sciences
Jianchuan Wang, Xianchi Dong, Bo Zhao, Jing Li, Chafen Lu, Timothy A. Springer
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2017)
Article
Biochemistry & Molecular Biology
Viet Q. Le, Roxana E. Iacob, Yuan Tian, William McConaughy, Justin Jackson, Yang Su, Bo Zhao, John R. Engen, Michelle Pirruccello-Straub, Timothy A. Springer
Article
Multidisciplinary Sciences
Xianchi Dong, Bo Zhao, Fu-Yang Lin, Chafen Lu, Bruce N. Rogers, Timothy A. Springer
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2018)
Article
Biochemistry & Molecular Biology
Bo Zhao, Patricia J. LiWang
Article
Medicine, Research & Experimental
Jie Xue, Yongguang Gao, Bart Hoorelbeke, Ioannis Kagiampakis, Bo Zhao, Borries Demeler, Jan Bazarini, Patricia J. LiWang
MOLECULAR PHARMACEUTICS
(2012)
Article
Biochemistry & Molecular Biology
Lin Qi, Zhong-Yong Wang, Xin-Rong Shao, Miao Li, Shu-Na Chen, Xue-Qi Liu, Shi Yan, Bo Zhang, Xu-Dong Zhang, Xin Li, Wenxue Zhao, Ji-An Pan, Bo Zhao, Xing-Ding Zhang
Article
Biochemistry & Molecular Biology
Liubing Du, Yanchun Xie, Kai Zheng, Niu Wang, Mingcheng Gao, Ting Yu, Liu Cao, QianQian Shao, Yong Zou, Wei Xia, Qianglin Fang, Bo Zhao, Deyin Guo, Xiaoxue Peng, Ji-An Pan
Summary: Our study reveals that oxidative stress can increase the overall activity of 3CLpro by reducing its solubility and leading to aggregation, while impairing the cellular antioxidant capacity. This activation mechanism involves the formation of disulfide bonds and cleavage of GPx1, resulting in a positive feedback loop that promotes viral replication/transcription. Therapeutic potential of antioxidants in treating COVID-19 patients is suggested by our findings.
Article
Virology
Ting Yu, Qiao Ling, Mengxin Xu, Niu Wang, Lixia Wang, Hanwen Lin, Manqi Cao, Yong Ma, Yuanyuan Wang, Kuibiao Li, Liubing Du, Yunyun Jin, Ying Li, Deyin Guo, Xiaoxue Peng, Yao-Qing Chen, Bo Zhao, Ji-An Pan
Summary: This study reveals the secretion mechanism of the ORF8 protein in coronaviruses and its impact on the reproductive system of mice. The findings provide a potential mouse model for investigating the effects of SARS-CoV-2 on the human reproductive system.
JOURNAL OF MEDICAL VIROLOGY
(2022)
Article
Biochemistry & Molecular Biology
Viet Q. Le, Roxana E. Iacob, Bo Zhao, Yang Su, Yuan Tian, Cameron Toohey, John R. Engen, Timothy A. Springer
Summary: Members of the transforming growth factor beta (TGF-beta) family play a fundamental role in organismal development and homeostasis. A comparative study using electron microscopy and hydrogen deuterium exchange revealed differences in conformation and dynamics between latent and non-latent members, as well as unique features that distinguish latent members.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Zelin Duan, Xuezhen Lin, Lixia Wang, Qiuxin Zhen, Yuefeng Jiang, Chuxin Chen, Jing Yang, Chia-Hsueh Lee, Yan Qin, Ying Li, Bo Zhao, Jianchuan Wang, Zhe Zhang
Summary: The authors elucidated the underlying mechanisms of specific presentation of L-TGF-beta 1 on the surface of myeloid lineage cells designated by LRRC33, and its activation by integrin alpha V beta 8.
NATURE COMMUNICATIONS
(2022)