key: cord-0997361-15bzy81p authors: Denel-Bobrowska, Marta; Olejniczak, Agnieszka B. title: Non-nucleoside structured compounds with antiviral activity—past 10 years (2010–2020) date: 2022-01-19 journal: Eur J Med Chem DOI: 10.1016/j.ejmech.2022.114136 sha: f6013353147b8738a60ae58285b6718c7873f30d doc_id: 997361 cord_uid: 15bzy81p Nucleosides and their derivatives are a well-known and well-described class of compounds with antiviral activity. Currently, in the era of the COVID-19 pandemic, scientists are also looking for compounds not related to nucleosides with antiviral properties. This review aims to provide an overview of selected synthetic antiviral agents not associated to nucleosides developed against human viruses and introduced to preclinical and clinical trials as well as drugs approved for antiviral therapy over the last 10 years. The article describes for the first time the wide classification of such antiviral drugs and drug candidates and briefly summarizes the biological target and clinical applications of the compounds. The described compounds are arranged according to the antiviral mechanism of action. Knowledge of the drug's activity toward specific molecular targets may be the key to researching new antiviral compounds and repositioning drugs already approved for clinical use. The paper also briefly discusses the future directions of antiviral therapy. The described examples of antiviral compounds can be helpful for further drug development. Viruses cause a broad spectrum of diseases, ranging from chronic to severe ones that may 24 lead to sudden death. Antiviral drug development began six decades ago, and the first 25 antiviral drug, nucleoside analog -idoxuridine, was described by William "Bill" Prusoff [1]. 26 Idoxuridine was used in the treatment of infant keratitis, which is caused by herpes simplex as new compounds, are applied or being developed for the treatment of COVID-19 [6, 7] . to-date information on the COVID-19 pandemic, in particular, the epidemiology, 49 pathogenesis, prevention and treatment strategies has been described in the following 50 publications [8, 9] . [12, 13] . Such methods are also helpful in the study of the 63 mechanisms of action of compounds, including the mechanism of drug resistancefor 64 example crystal structures of influenza virus polymerase basic protein 2 (PB2) and pimodivir Particularly noteworthy is the review published by Lin and colleagues [29] in 2021, 126 describing individual modifications of the structure of nucleoside analogues and the 127 mechanism of their antiviral activity. Importantly, the authors describe the influence of 128 particular structural modifications on the biological activity of compounds. The present review aims to provide an overview of selected antiviral agents not related to 136 nucleosides. The drugs described in this paper were developed over the past 10 years. The 137 compounds have been ordered according to the mechanism of action. A brief description is 138 also made of future directions of antiviral therapy. Table 1) is an 177 orally bioavailable antiviral compound. Its mechanism of action is based on the inhibition of 178 respiratory syncytial virus (RSV, Paramyxoviridae family) fusion with host cell membranes. The piperidine ring has been revealed to facilitate the formation of an appropriate dihedral indicated that tegobuvir showed high potency in vitro [55] . According to reports from phase 1 255 clinical trials [56, 57] , the drug induced QT prolongation at high doses. Therefore, its further 256 development was limited to a dose of 40 mg [56] . Basing on the promising results observed in the in vitro studies of tegobuvir, Liu's team [57] 258 designed and synthesized a series of novel inhibitors of HCV NS5B polymerase to improve 259 the antiviral activity and reduce the adverse effects of tegobuvir. However, only one of the 260 investigated compounds showed beneficial effects and safety and was selected for further 261 studies [57] . HCV genotype 1 or 4 infections in adults [94] . Glecaprevir is a component of Mavyret™ (Table 2) Table 2 ). In addition, were approved as components of drugs approved for the treatment of HCV (Table 2, trade 459 names Harvoni and Epclusa ® , respectively). performed not only among nucleoside analogues but also not related to nucleosides chemical 528 compounds. The adenosine analogue islatravir is an example of a new nucleoside analogue 529 that has been successfully introduced into phase 3 clinical trials as an anti-HIV agent. ABX464 is an example of a non-nucleoside derivative that has entered phase 3 clinical trials. The antimalarial drug chloroquine, an example of drug repositioning, has currently completed Scientists are also interested in using biologically active metabolites in antiviral therapy. Such 536 compounds have been considered for antiviral therapy and prophylaxis, due to their antioxidant, antibacterial, antifungal, and antiviral activities [128] . Articles published by 538 Singh and colleagues, and Bibi and co-workers, describe the antiviral efficacy of plant-based SARS-CoV-2 Mpro 601 inhibitors and activity-based probes for patient-sample imaging Structure-based design of 606 antiviral drug candidates targeting the SARS-CoV-2 main protease Structural 609 and thermodynamic analysis of the resistance development to Pimodivir (VX-787), the 610 clinical inhibitor of cap binding to PB2 subunit of influenza a polymerase Protection against filovirus diseases by a novel broad-spectrum nucleoside 640 analogue BCX4430 Antiviral drugs against severe acute respiratory syndrome coronavirus 2 642 infection triggering the coronavirus disease-19 pandemic A contemporary look at COVID-19 medications: Available 645 and potentially effective drugs FDA's approval of Veklury (remdesivir) for the treatment of COVID-19 Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis CoV-2 mutagenesis via the RNA template Molnupiravir: coding for catastrophe Approved antiviral drugs over the past 50 years Advance of structural 663 modification of nucleosides scaffold 4′-modified 668 nucleoside analogs: Potent inhibitors active against entecavir-resistant hepatitis B virus Effectively Inhibits SARS-CoV-2 Infection in Mouse Models 2′-Fluoro-6′-methylene carbocyclic 675 adenosine and its phosphoramidate prodrug: A novel anti-HBV agent, active against 676 drug-resistant HBV mutants The Viral 679 Polymerase Inhibitor 7-Deaza-2'-C-Methyladenosine Is a Potent Inhibitor of In Vitro 680 Zika Virus Replication and Delays Disease Progression in a Robust Mouse Infection 681 Resistance analysis and characterization of NITD008 as an adenosine analog inhibitor 685 against hepatitis C virus Pharmacokinetics studies of 4′-cyano-2′-deoxyguanosine, a potent inhibitor 689 of the hepatitis B virus, in rats CMCDG, a 693 novel nucleoside analog with favorable safety features, exerts potent activity against 694 wild-type and entecavir-resistant hepatitis B virus Antiviral activity of FNC, 2′-deoxy-2′-β-fluoro-4′-azidocytidine, 698 against human and duck HBV replication Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside 703 viral replication inhibitor, in experimentally infected humans A general and 706 enantioselective approach to pentoses: A rapid synthesis of PSI-6130, the nucleoside 707 core of sofosbuvir Remdesivir and chloroquine effectively inhibit the recently emerged novel 711 coronavirus (2019-nCoV) in vitro Emergence of novel coronavirus and 714 progress toward treatment and vaccine GS-5806 inhibits a 718 broad range of respiratory syncytial virus clinical isolates by blocking the virus-cell 719 fusion process Oral GS-5806 724 activity in a respiratory syncytial virus challenge study Discovery of an oral 730 respiratory syncytial virus (RSV) fusion inhibitor (GS-5806) and clinical proof of 731 concept in a human RSV challenge study multicenter study evaluating antiviral effects, pharmacokinetics, safety, and tolerability 738 of presatovir in hematopoietic cell transplant recipients with respiratory syncytial virus 739 infection of the Central nervous system disposition and metabolism of 743 Fosdevirine (GSK2248761), a non-nucleoside reverse transcriptase inhibitor: An LC-744 MS and matrix-assisted laser desorption/ionization imaging MS investigation into 745 central nervous system toxicity Single-dose escalation and multiple-dose safety, tolerability, and 749 pharmacokinetics of IDX899, a candidate human immunodeficiency virus type 1 750 nonnucleoside reverse transcriptase inhibitor, in healthy subjects Unexpected finding of delayed-onset seizures in HIV-positive, treatment-754 experienced subjects in the phase IIb evaluation of fosdevirine (GSK2248761) A phase 2a trial 766 of 12-week interferon-free therapy with two direct-acting antivirals (ABT-450/r, ABT-767 072) and ribavirin in IL28B C/C patients with chronic hepatitis C genotype 1 Discovery of GS-9669, a thumb site 773 II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C 774 infection Thumb site 2 inhibitors of hepatitis C viral RNA-dependent RNA 776 polymerase allosterically block the transition from initiation to elongation NS5B polymerase 779 inhibitors in phase II clinical trials for HCV infection Mechanistic 784 characterization of GS-9190 (tegobuvir), a novel nonnucleoside inhibitor of hepatitis C 785 virus NS5B polymerase The HCV non-nucleoside 790 inhibitor tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase 791 function Nucleoside, nucleotide, 793 and non-nucleoside inhibitors of hepatitis C virus NS5B RNA-dependent RNA-794 Design, 796 synthesis, and structure-activity relationships of novel imidazo[4,5-c]pyridine 797 derivatives as potent non-nucleoside inhibitors of hepatitis C virus NS5B Pharmacokinetics and pharmacodynamics of setrobuvir, an orally administered 801 hepatitis C virus non-nucleoside analogue inhibitor A 804 pharmacokinetic/viral kinetic model to evaluate treatment of chronic HCV infection 805 with a non-nucleoside polymerase inhibitor SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in 808 silico perspective Preclinical characterization of PC786, an inhaled small-molecule 814 respiratory syncytial virus L protein polymerase inhibitor Late therapeutic 818 intervention with a respiratory syncytial virus L-protein polymerase inhibitor, PC786, 819 on respiratory syncytial virus infection in human airway epithelium Antivirals targeting the polymerase complex of 822 influenza viruses Activities of JNJ63623872 and oseltamivir 825 against influenza A H1N1pdm and H3N2 virus infections in mice Phase 2b study of pimodivir (JNJ-829 63623872) as monotherapy or in combination with oseltamivir for treatment of acute 830 uncomplicated seasonal influenza A: TOPAZ trial Discovery of RG7834: The First-in-841 Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression 842 Inhibitor with Novel Mechanism of Action A novel orally available small molecule that 848 inhibits hepatitis B virus expression GS-9620, an 852 oral agonist of toll-like receptor-7, induces prolonged suppression of hepatitis B virus 853 in chronically infected chimpanzees Safety, 857 pharmacokinetics and pharmacodynamics of GS-9620, an oral Toll-like receptor 7 858 agonist 860 hepatitis B who are not currently on antiviral treatment Safety, efficacy and pharmacodynamics of 867 vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis Discovery of GS-9688 (Selgantolimod) as a Potent and Selective Oral Toll-873 Like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B In vitro inhibition of HBV 877 replication by a novel compound, GLS4, and its efficacy against adefovirdipivoxil-878 resistant HBV mutations GLS4, an inhibitor of Hepatitis B virus core particle assembly Discovery 885 of hepatitis B virus capsid assembly inhibitors leading to a 25 -Bromo-4-fluorophenyl)-5-890 (ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2 Acid (HEC72702), a Novel Hepatitis B Virus Capsid Inhibitor Based on 892 Clinical Candidate GLS4 Long lasting 897 control of viral rebound with a new drug ABX464 targeting Rev -mediated viral RNA 898 biogenesis Vandekerckhove, Safety, tolerability and impact on viral 901 reservoirs of the addition to antiretroviral therapy of ABX464, an investigational 902 antiviral drug, in individuals living with HIV-1: A Phase IIa randomised controlled 903 study Which antivirals for the coming 905 decade? Entry Inhibitors: Efficient Means to Block Viral 908 Development of novel entry inhibitors targeting emerging 911 viruses Some 7-Substituted 4-Aminoquinoline Derivatives Perspectives for repurposing drugs for the coronavirus disease CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties Pharmacological and cardiovascular perspectives on the treatment of COVID-19 with 923 chloroquine derivatives Efficacy and 926 safety of abacavir/lamivudine plus rilpivirine as a first-line regimen in treatment HIV-1 infected adults Pharmaceutical, 930 clinical, and resistance information on doravirine, a novel non-nucleoside reverse 931 transcriptase inhibitor for the treatment of HIV-1 infection Influenza and antiviral resistance: an overview Telaprevir/boceprevir era: 939 From bench to bed and back Simeprevir 942 for the treatment of hepatitis C virus infection Biochemical Basis of Vosevi, a New Treatment for Hepatitis 945 Grazoprevir/elbasvir for the treatment of adults with chronic 947 hepatitis C: a short review on the clinical evidence and place in therapy Glecaprevir/pibrentasvir for the treatment of chronic 950 hepatitis C: Design, development, and place in therapy Darunavir/cobicistat for the treatment of HIV-1: 953 A new era for compact drugs with high genetic barrier to resistance Dolutegravir-Based Antiretroviral Regimens for HIV Liver Transplant 957 Patients in Real-Life Settings Targeting Integrase 960 Enzyme: A Therapeutic Approach to Combat HIV Resistance, Mini-Reviews Med Peramivir injection in the treatment of acute influenza: A 963 review of the literature Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy, Curr In vitro 969 and in vivo antiviral activity and resistance profile of ombitasvir, an inhibitor of 970 hepatitis C virus NS5A Comparative efficacy of sofosbuvir-974 ribavirin versus sofosbuvir-daclatasvir for treatment of chronic hepatitis C in an area 975 with limited NS5A inhibitor availability Real-life 979 experience of ledipasvir and sofosbuvir single-tablet regimen among chronic hepatitis 980 C patients in Turkey Sofosbuvir and velpatasvir for the treatment of hepatitis 983 FDA Drug Approvals and Databases Alkylaminoalkyl)pyrazolo[1,5-a]pyrimidines as New Respiratory Syncytial Virus 991 RNA-dependent RNA polymerase (RdRp) inhibitors: The current 995 landscape and repurposing for the COVID-19 pandemic Mechanisms of inhibition of HIV replication by non-998 nucleoside reverse transcriptase inhibitors The 1001 development of an effective synthetic route of rilpivirine Hepatitis C Viruses: Genomes and 1005 Molecular Biology Structural basis of viral RNA-dependent RNA polymerase catalysis 1008 and translocation hepatitis C virus non-nucleoside analogue inhibitor Molecular Dynamics Simulation reveals the 1015 mechanism by which the Influenza Cap-dependent Endonuclease acquires resistance 1016 against Baloxavir marboxil Molecular docking based drug repurposing study of antiviral drugs against COVID-19 1020 virus spike receptor binding domain Computational Investigation of the Interaction of Anti-Influenza 1022 Drugs with CoVID-19 Protein Clinical Trial and Synthesis Progress of Small Molecules for the Treatment of COVID-1026 19 Computationally repurposed drugs 1028 and natural products against RNA dependent RNA polymerase as potential COVID-19 1029 therapies Drug Repurposing Strategy (DRS): Emerging Approach to Identify Potential 1032 Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against 1035 SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study That Are Required for Hepatitis B Virus RNA Stabilization Protease inhibitors as antiviral agents Ring-Closing Metathesis on Commercial 1045 Scale: Synthesis of HCV Protease Inhibitor Simeprevir Progress in HIV-1 integrase inhibitors: A review of their 1048 chemical structure diversity FDA's Clinical Pharmacology review Neuraminidase inhibitors as antiviral agents Phosphorylation of hepatitis C 1057 virus NS5A nonstructural protein: A new paradigm for phosphorylation-dependent 1058 viral RNA replication? Inhibition of hepatitis B virus replication by drug-induced depletion of 1064 nucleocapsids Flavonoids: promising natural compounds 1066 against viral infections Phytotherapic 1069 Drugs for COVID-19 Treatment: A Scoping Review Impact of Traditional Plants and their Secondary 1073 Metabolites in the Discovery of COVID-19 Treatment An overview of functional nanoparticles as novel emerging antiviral 1076 therapeutic agents Identifying 1079 potential biomarkers in hepatitis B virus infection and its response to the antiviral 1080 therapy by integrated bioinformatic analysis Approaches for COVID-19 Antibody therapies for the prevention and Antiviral Monoclonal Antibodies Can They Be More Than Simple Neutralizing Agents? FDA authorized the use of bamlanivimab for the treatment of mild-to-moderate 1092 COVID-19 in adult and pediatric patients CRISPR-cas: Biology, mechanisms and relevance The CRISPR/Cas9 1100 system facilitates clearance of the intrahepatic HBV templates in vivo The Potential Use of the 1103 CRISPR-Cas System for HIV-1 Gene Therapy