Review
Chemistry, Medicinal
Yanping Li, Bo Yang, Yanni Quan, Zhuorong Li
Summary: In the past decades, synthetic nucleoside or nucleotide analogues have been crucial for the development of antiviral agents, but their biological activity is often hindered by low membrane permeability and insufficient cellular phosphorylation. To overcome these limitations, diverse lipophilic prodrug modifications, particularly the ProTide technology, have been successful in delivering nucleosides into the target site and bypassing the rate-limited phosphorylation step, leading to the discovery of FDA-approved antiviral agents.
CURRENT TOPICS IN MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Kevin J. Sparrow, Rinu Shrestha, James M. Wood, Keith Clinch, Brett L. Hurst, Hong Wang, Brian B. Gowen, Justin G. Julander, E. Bart Tarbet, Alice M. McSweeney, Vernon K. Ward, Gary B. Evans, Lawrence. D. Harris
Summary: We report the antiviral activities of two iminovirs (antiviral imino-C-nucleosides) 1 and 2, structurally related to galidesivir (Immucillin A, BCX4430), for the first time. An iminovir containing the 4-aminopyrrolo[2,1-f ][1,2,4-triazine] nucleobase found in remdesivir showed submicromolar inhibition against multiple strains of influenza A and B viruses, as well as members of the Bunyavirales order. The ProTide prodrugs of iminovir monophosphates displayed poorer viral inhibition than their parent nucleosides in vitro. A synthesized iminovir 2 containing 4-aminopyrrolo[2,1-f][1,2,4-triazine] was used for preliminary in vivo studies, but it showed significant toxicity in BALB/ c mice and limited protection against influenza, indicating the need for further modification to improve its therapeutic value.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Review
Pharmacology & Pharmacy
Michaela Serpi, Fabrizio Pertusati
Summary: The ProTide technology, a phosphate prodrug method, has been successful in delivering new antiviral drugs and shows promise in oncology. Its application to non-nucleoside-based small molecules is emerging and proving effective in various therapeutic areas. Investigations to explain the lack of activity of certain ProTide series and comprehensive structure activity relationship studies are deemed necessary for the future development of these compounds.
EXPERT OPINION ON DRUG DISCOVERY
(2021)
Review
Chemistry, Medicinal
Leandro S. de Mariz e Miranda
Summary: This viewpoint proposes that molecules inhibiting nucleotide biosynthesis may sensitize virus-infected cells to antiviral nucleosides, potentially leading to the development of new combination therapies.
ARCHIV DER PHARMAZIE
(2023)
Article
Chemistry, Organic
Jie Yao, Chengjie Huang, Fan Wu, Yufen Zhao, Feng Ni
Summary: Drug development based on phenolic natural products has gained attention, but poor bioavailability limits their clinical use. This paper presents a prodrug approach to improve bioavailability and synthesis of various phosphoramidate prodrugs from phenolic drugs. The method also allows selective phosphorylation of the phenolic hydroxyl group in the presence of nucleophilic functional groups.
SYNTHESIS-STUTTGART
(2022)
Article
Chemistry, Medicinal
Linjie Yan, Ruiyuan Cao, Hongjie Zhang, Yuexiang Li, Wei Li, Xiaoyuan Li, Shiyong Fan, Song Li, Wu Zhong
Summary: Phosphoamidate derivatives of nucleoside NITD008 were synthesized and evaluated for their antiviral activities against EV71 and EV-D68, with compounds 15f and 151 showing the most promising results. Compound 151 demonstrated the highest selectivity index against both viruses, indicating its potential as a candidate for antiviral drug development in treating EV71 and EV-D68 infections.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Richard L. Mackman
Summary: Remdesivir is a prodrug that delivers nucleoside monophosphate inhibitors to lung cells, providing antiviral activity against RNA viruses such as coronaviruses. Its potential in respiratory virus treatment warrants further investigation.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Multidisciplinary
Longhu Zhou, Hongwang Zhang, Chengwei Li, Coralie De Schutter, Ozkan Sari, Seema Mengshetti, Shaoman Zhou, Mahesh Kasthuri, Steven J. Coats, Raymond F. Schinazi, Franck Amblard
Summary: A newly developed synthetic route was presented for the synthesis of 2-bromo-2-fluoro ribolactone, based on a previously published synthesis. Improved glycosylation reactions were reported for both 2-bromo-2-fluoro and 2-chloro-2-fluoro sugars, resulting in an overall yield of 15-20% for the preparation of 2'-dihalo nucleosides.
Article
Biochemical Research Methods
Heena Tarannum, Sisir Nandi
Summary: This study utilized structure-based molecular docking to repurpose RNA-dependent RNA polymerase inhibitors from dengue virus, yellow fever virus, and Zika virus for the treatment of hepatitis C virus (HCV). Several compounds were identified as potential leads for further testing and repurposing to combat HCV.
COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING
(2022)
Article
Biochemistry & Molecular Biology
Di Han, Huiqun Wang, Baerlike Wujieti, Beibei Zhang, Wei Cui, Bo-Zhen Chen
Summary: This study elucidates the resistance mechanisms of GS-9669 caused by mutations in the NS5B polymerase of HCV, showing that these mutations reduce the binding affinity and can lead to different degrees of resistance. The results provide valuable insights for further optimization and design of novel NS5B inhibitors.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Pharmacology & Pharmacy
Kiran S. Toti, Nicole Pribut, Michael D'Erasmo, Madhuri Dasari, Savita K. Sharma, Perry W. Bartsch, Samantha L. Burton, Hannah B. Gold, Anatoliy Bushnev, Cynthia A. Derdeyn, Adriaan E. Basson, Dennis C. Liotta, Eric J. Miller
Summary: Nucleoside- and nucleotide-based therapeutics play crucial roles in treating malignant and viral diseases. Prodrugs, commonly used for improving bioavailability and efficacy, can be optimized with small adjustments to enhance pharmacokinetic profiles. In this study, the fine-tuning of lipid prodrugs of tenofovir, a nucleotide HIV reverse transcriptase inhibitor, successfully reduced liver omega-oxidation while maintaining potent antiviral activity. This research provides important insights into lipid prodrug strategies and the delivery of acyclic nucleoside phosphonates.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Microbiology
Julia C. LeCher, Keivan Zandi, Vivian Vasconcelos Costa, Franck Amblard, Sijia Tao, Dharmeshkumar Patel, Sujin Lee, Felipe Rocha da Silva Santos, Matheus Rodrigues Goncalves, Celso Martins Queroz-Junior, Fernanda Martins Marim, Katie Musall, Shu Ling Goh, Tamara McBrayer, Jessica Downs-Bowen, Ramyani De, Niloufar Azadi, James Kohler, Mauro Martins Teixeira, Raymond F. Schinazi
Summary: This study reports potential antiviral drugs against yellow fever virus, showing low toxicity, high intracellular metabolism, and strong anti-YFV activity in different models. The findings provide a new therapeutic option for treating yellow fever virus infections.
Article
Biochemistry & Molecular Biology
Simon Gonzalez, Gabriela Brzuska, Abdelhakim Ouarti, Florian Gallier, Carmen Solarte, Angelique Ferry, Jacques Uziel, Ewelina Krol, Nadege Lubin-Germain
Summary: The compound 2 carrying an N-hydroxy carboxamide function exhibited the most inhibitory activities against both Zika virus (ZIKV) and hepatitis C virus (HCV), suggesting it could be a potential candidate for the development of new anti-HCV and anti-ZIKV drugs.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Mengbi Yang, Xin Xu
Summary: Nucleoside analogs are important antiviral agents, but their hydrophilicity and limited membrane permeability require the involvement of transporters in their pharmacokinetics. This review discusses the roles of transporters in the pharmacokinetics of 25 approved AVNAs and highlights the impact of co-administered inhibitors and genetic polymorphisms of transporters on AVNA pharmacokinetics. More research is needed to understand the roles of transporters in the distribution of AVNAs, especially in immune privileged compartments. Pharmacokinetic models can be useful in elucidating the complex factors affecting AVNA pharmacokinetics in clinical settings.
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
(2022)
Editorial Material
Chemistry, Medicinal
Victoria C. Yan
Summary: Remdesivir is an FDA-approved drug for COVID-19 treatment that has shown broad-spectrum antiviral activity in preclinical models. However, its clinical efficacy varies. This study highlights the discordance between humans and non-human primates in the pharmacodynamic effect of remdesivir.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Multidisciplinary Sciences
Daniel L. Hurdiss, Priscila El Kazzi, Lisa Bauer, Nicolas Papageorgiou, Francois P. Ferron, Tim Donselaar, Arno L. W. van Vliet, Tatiana M. Shamorkina, Joost Snijder, Bruno Canard, Etienne Decroly, Andrea Brancale, Tzviya Zeev-Ben-Mordehai, Friedrich Forster, Frank J. M. van Kuppeveld, Bruno Coutard
Summary: This study reveals the crystal structure of the binding complex between enterovirus 2C protein and fluoxetine, uncovering an allosteric binding site. By engineering a hexameric form of 2C protein, the study demonstrates that compounds like fluoxetine can inhibit the ATPase activity of 2C. Cryo-electron microscopy analysis further shows how fluoxetine locks 2C protein in a hexameric state. These findings provide important insights into the inhibition mechanism of 2C and offer a robust engineering strategy for studying its structure, function, and drug-screening analysis.
Article
Biology
Anoop Narayanan, Manju Narwal, Sydney A. Majowicz, Carmine Varricchio, Shay A. Toner, Carlo Ballatore, Andrea Brancale, Katsuhiko S. Murakami, Joyce Jose
Summary: In this study, a screening strategy for antiviral drugs against SARS-CoV-2 was developed, which involves in-cell protease assay, antiviral and biochemical activity assessments, as well as structural determinations. Several protease inhibitors with low cytotoxicity were identified and their mechanisms of action were examined.
COMMUNICATIONS BIOLOGY
(2022)
Article
Chemistry, Medicinal
Romeo Romagnoli, Paola Oliva, Filippo Prencipe, Stefano Manfredini, Federica Budassi, Andrea Brancale, Salvatore Ferla, Ernest Hamel, Diana Corallo, Sanja Aveic, Lorenzo Manfreda, Elena Mariotto, Roberta Bortolozzi, Giampietro Viola
Summary: A study was conducted to synthesize a series of new compounds with potential antitumor activity. Among these compounds, three showed significantly higher activity compared to others. These compounds demonstrated strong antiproliferative effects on different cancer cell lines and were able to induce apoptosis through various mechanisms. In vivo experiments using a zebrafish model also showed promising results in reducing tumor mass.
Article
Pharmacology & Pharmacy
Carmine Varricchio, Gregory Mathez, Trestan Pillonel, Claire Bertelli, Laurent Kaiser, Caroline Tapparel, Andrea Brancale, Valeria Cagno
Summary: Aminoglycoside antibiotic gentamicin has been found to effectively combat various variants of SARS-CoV-2 in different cell lines and respiratory tissue models. It inhibits viral RNA replication and protein expression at an early stage by targeting the ribosomal frameshift signal of SARS-CoV-2.
ANTIVIRAL RESEARCH
(2022)
Article
Chemistry, Medicinal
Martina Salerno, Carmine Varricchio, Federica Bevilacqua, Dirk Jochmans, Johan Neyts, Andrea Brancale, Salvatore Ferla, Marcella Bassetto
Summary: Different viruses, such as enterovirus 71, rely on the host enzyme METTL3 to complete their cytoplasmic life cycle stages. By modulating the activity of this enzyme, it is possible to interfere with a broad range of viral infections. In this study, a series of nucleoside analogues were designed as inhibitors of human METTL3 to target multiple viral infections. Through molecular docking studies and synthesis, several novel and potent inhibitors of enterovirus 71 were identified.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Francesca Picarazzi, Marika Zuanon, Gaia Pasqualetto, Silvia Cammarone, Isabella Romeo, Mark T. Young, Andrea Brancale, Marcella Bassetto, Mattia Mori
Summary: A computational-boosted workflow was used to select potential chaperones for P23H opsins using homology modeling, molecular dynamics simulations, and virtual screening. In vitro studies confirmed the reliability of the generated structural model and identified new chemotypes of safe and effective chaperones that can enhance P23H opsin trafficking to the outer cell membrane.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Thibault Alle, Carmine Varricchio, Yuemang Yao, Bobby Lucero, Goodwell Nzou, Stefania Demuro, Megan Muench, Khoa D. Vuong, Killian Oukoloff, Anne-Sophie Cornec, Karol R. Francisco, Conor R. Caffrey, Virginia M. -Y. Lee, Amos B. Smith III, Andrea Brancale, Kurt R. Brunden, Carlo Ballatore
Summary: Researchers designed, synthesized, and evaluated a series of new triazolo[1,5-a]-pyrimidine compounds, and further elucidated the structure-activity relationships of these compounds through matched molecular pair analyses and computational studies. The study identified novel microtubule-stabilizing triazolo[1,5-a]-pyrimidine candidates that exhibited favorable ADME-PK properties, including brain penetration and oral bioavailability, as well as brain pharmacodynamic activity.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Virology
Gilda Giancotti, Giulio Nannetti, Gilda Padalino, Martina Landini, Nanci Santos-Ferreira, Jana Van Dycke, Valentina Naccarato, Usheer Patel, Romano Silvestri, Johan Neyts, Roberto Gozalbo-Rovira, Jesus Rodriguez-Diaz, Joana Rocha-Pereira, Andrea Brancale, Salvatore Ferla, Marcella Bassetto
Summary: Human norovirus is the leading cause of foodborne diseases worldwide, resulting in severe acute gastroenteritis outbreaks and causing approximately 200,000 deaths in children in developing countries annually. Current treatment options are limited to supportive care, highlighting the urgent need for antiviral agents. In this study, we focused on the viral RNA-dependent RNA polymerase (RdRp) as a potential target for antiviral drug discovery. By rationally modifying identified scaffolds, we synthesized new compounds with improved inhibition of RdRp, providing a promising foundation for further optimization.
Article
Pharmacology & Pharmacy
Gaia Pasqualetto, Marika Zuanon, Andrea Brancale, Mark T. Young
Summary: The ATP-gated ion channels P2X4 and P2X7 receptors are drug targets for inflammatory pain. Through virtual screening, a compound (GP-25) was found to display antagonist activity at human P2X7 but not at human P2X4. Further screening led to the discovery of five additional compounds with antagonist activity at human P2X7. Docking experiments revealed the structural basis for the lack of activity of GP-25 at human P2X4.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Jessica R. Spengler, Stephen R. Welch, Jerome Deval, Brian G. Gentry, Andrea Brancale, Kara Carter, Jennifer Moffat, Chris Meier, Katherine L. Seley-Radtke, Luis M. Schang
Summary: The 35th International Conference on Antiviral Research (ICAR) was held in Seattle, Washington, USA, on March 21-25, 2022, and via an interactive remote meeting platform. This report provides an overview of the conference, summarizing presentations and key conclusions from researchers in various areas of antiviral research and development. The conference showcased efforts and advancements in the field and demonstrated the significant response to the ongoing pandemic while emphasizing the importance of future pandemic preparedness.
ANTIVIRAL RESEARCH
(2023)
Article
Chemistry, Physical
Haoyue Xiang, Salvatore Ferla, Carmine Varricchio, Andrea Brancale, Nicola L. Brown, Gary W. Black, Nicholas J. Turner, Daniele Castagnolo
Summary: Two enzymatic strategies were developed to oxidize 1,2,3,4-tetrahydroquinolines (THQs) and N-cyclopropyl-N-alkylanilines into quinolines and 2-quinolones, respectively. Whole cells and monoamine oxidase (MAO-N) enzymes were used for the biotransformation of THQs, while horseradish peroxidase (HRP)-catalyzed annulation/aromatization reaction followed by Fe-mediated oxidation was employed for the conversion of N-cyclopropyl-N-alkylanilines into 2-quinolone compounds.
Article
Pharmacology & Pharmacy
Gaia Pasqualetto, Marika Zuanon, Andrea Brancale, Mark T. Young
Summary: P2X receptors are ATP-gated cation channels that play key roles in nerve transmission, pain sensation, and inflammation. P2X4 receptor has attracted interest from pharmaceutical companies due to its roles in neuropathic pain and vascular tone modulation. A study confirmed the importance of a specific amino acid (I312T) for the sensitivity of the P2X4 receptor antagonist BX430 and identified a plausible binding pocket for a series of P2X4 antagonists.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Karol R. Francisco, Jessica Bruystens, Carmine Varricchio, Sara Mccurdy, Jian Wu, Miguel A. Lopez-Ramirez, Mark Ginsberg, Conor R. Caffrey, Andrea Brancale, Alexandre R. Gingras, Mark S. Hixon, Carlo Ballatore
Summary: The covalent reversible modification of proteins is an important strategy for the development of probes and candidate therapeutics. In this study, the 2-hydroxy-1-naphthaldehyde (HNA) fragment is characterized as a targeted covalent reversible ligand of a noncatalytic lysine on the KRIT1 protein. HNA shows high specificity in its interaction with KRIT1, leading to prolonged residence time and inhibition of the HEG1-KRIT1 protein-protein interaction. Screening of HNA derivatives identified analogs with faster target engagement and stronger inhibition activity.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Review
Chemistry, Medicinal
Luis Queiros-Reis, Joao R. Mesquita, Andrea Brancale, Marcella Bassetto
Summary: This review discusses the fatty acid binding pocket (FABP) in the spike glycoprotein of SARS-CoV-2 and its ligands with antiviral activity. Compounds that stabilize the inactive conformation of the spike protein and reduce viral infectivity show potential for the development of broad-spectrum antiviral agents.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Meeting Abstract
Ophthalmology
Pete A. Williams, James R. Tribble, Melissa Joe, Andrea Brancale, Carmine Varricchio, Michael Coleman, Jonathan Gilley, Andrea Loreto, Craig Wheelock, Gauti Johannesson
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2022)
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)
