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1.
Eur J Med Chem ; 277: 116768, 2024 Nov 05.
Article in English | MEDLINE | ID: mdl-39163780

ABSTRACT

Influenza viruses that cause seasonal and pandemic flu are a permanent health threat. The surface glycoprotein, neuraminidase, is crucial for the infectivity of the virus and therefore an attractive target for flu drug discovery campaigns. We have designed and synthesized more than 40 3-indolinone derivatives. We mainly investigated the role of substituents at the 2 position of the core as well as the introduction of substituents or a nitrogen atom in the fused phenyl ring of the core for inhibition of influenza virus neuraminidase activity and replication in vitro and in vivo. After evaluating the compounds for their ability to inhibit the viral neuraminidase, six potent inhibitors 3c, 3e, 7c, 12o, 12v, 18d were progressed to evaluate for cytotoxicity and inhibition of influenza virus A/PR/8/34 replication in in MDCK cells. Two hit compounds 3e and 12o were tested in an animal model of influenza virus infection. Molecular mechanism of the 3-indolinone derivatives interactions with the neuraminidase was revealed in molecular dynamic simulations. Proposed inhibitors bind to the 430-cavity that is different from the conventional binding site of commercial compounds. The most promising 3-indolinone inhibitors demonstrate stronger interactions with the neuraminidase in molecular models that supports proposed binding site.


Subject(s)
Antiviral Agents , Enzyme Inhibitors , Indoles , Neuraminidase , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Indoles/pharmacology , Indoles/chemistry , Indoles/chemical synthesis , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Animals , Dogs , Structure-Activity Relationship , Madin Darby Canine Kidney Cells , Molecular Structure , Models, Molecular , Influenza A virus/drug effects , Influenza A virus/enzymology , Dose-Response Relationship, Drug , Chemistry, Pharmaceutical , Humans , Mice , Microbial Sensitivity Tests , Virus Replication/drug effects
2.
Viruses ; 16(6)2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38932280

ABSTRACT

Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are widespread human pathogens that establish chronic latent infections leading to recurrent episodes. Current treatments are limited, necessitating the development of novel antiviral strategies. This study aimed to assess the antiviral efficacy of novel topical formulations containing interferon alpha-2b (IFN α-2b) against HSV-1 and HSV-2. The formulations, Oftalmoferon® forte (eye drops) and Interferon Vaginal Tablets, demonstrated potent antiviral effects against HSV-1 and HSV-2 in Vero cells, respectively, with concentration-dependent inhibition of viral replication. Subsequently, their efficacy was tested in animal models: HSV-1 keratitis in the rabbit eye model and HSV-2 genital herpes in mice. Oftalmoferon® forte effectively treated HSV-1 keratitis, reducing clinical symptoms and ulcerations compared to virus control. Interferon Vaginal Tablets showed promising results in controlling HSV-2 genital herpes in mice, improving survival rates, reducing clinical signs, weight loss and viral replication. The novel IFN α-2b formulations exhibited significant antiviral activity against HSV infections in cell culture and animal models. These findings suggest the potential of these formulations as alternative treatments for HSV infections, particularly in cases resistant to current therapies. Further studies are warranted to optimize treatment regimens and assess clinical efficacy in humans.


Subject(s)
Antiviral Agents , Disease Models, Animal , Herpes Genitalis , Herpesvirus 1, Human , Herpesvirus 2, Human , Keratitis, Herpetic , Animals , Rabbits , Herpesvirus 1, Human/drug effects , Herpesvirus 2, Human/drug effects , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Mice , Herpes Genitalis/drug therapy , Herpes Genitalis/virology , Keratitis, Herpetic/drug therapy , Keratitis, Herpetic/virology , Chlorocebus aethiops , Female , Vero Cells , Interferon alpha-2/administration & dosage , Interferon alpha-2/therapeutic use , Virus Replication/drug effects , Administration, Topical , Ophthalmic Solutions , Interferon-alpha/administration & dosage , Humans
3.
J Antimicrob Chemother ; 76(4): 1010-1018, 2021 03 12.
Article in English | MEDLINE | ID: mdl-33367751

ABSTRACT

BACKGROUND: The development and clinical implementation of the cap-dependent endonuclease (CEN) inhibitor baloxavir marboxil was a breakthrough in influenza therapy, but it was associated with the emergence of drug-resistant variants. OBJECTIVES: To design and synthesize structural analogues of CEN inhibitors and evaluate their safety, pharmacokinetics and antiviral potency in vitro and in vivo. METHODS: The drug candidate AV5124 and its active metabolite AV5116 were synthesized based on pharmacophore modelling. Stability in plasma and microsomes, plasma protein binding, cytotoxicity and antiviral activities were assessed in vitro. Pharmacokinetics after IV or oral administration were analysed in CD-1 mice. Acute toxicity and protective efficacy against lethal A(H1N1)pdm09 influenza virus challenge were examined in BALB/c mice. RESULTS: Pharmacophore model-assisted, 3D molecular docking predicted key supramolecular interactions of the metal-binding group and bulky hydrophobic group of AV5116 with the CEN binding site (Protein Data Bank code: 6FS6) that are essential for high antiviral activity. AV5116 inhibited influenza virus polymerase complexes in cell-free assays and replication of oseltamivir-susceptible and -resistant influenza A and B viruses at nanomolar concentrations. Notably, AV5116 was equipotent or more potent than baloxavir acid (BXA) against WT (I38-WT) viruses and viruses with reduced BXA susceptibility carrying an I38T polymerase acidic (PA) substitution. AV5116 exhibited low cytotoxicity in Madin-Darby canine kidney cells and lacked mitochondrial toxicity, resulting in favourable selective indices. Treatment with 20 or 50 mg/kg AV5124 prevented death in 60% and 100% of animals, respectively. CONCLUSIONS: Overall, AV5124 and A5116 are promising inhibitors of the influenza virus CEN and warrant further development as potent anti-influenza agents.


Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza, Human , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Dibenzothiepins , Dogs , Endonucleases , Humans , Influenza, Human/drug therapy , Mice , Mice, Inbred BALB C , Molecular Docking Simulation , Morpholines , Pyridones , Triazines
4.
J Med Chem ; 63(17): 9403-9420, 2020 09 10.
Article in English | MEDLINE | ID: mdl-32787099

ABSTRACT

4-Substituted 2,4-dioxobutanoic acids inhibit influenza virus cap-dependent endonuclease (CEN) activity. Baloxavir marboxil, 4, is approved for treating influenza virus infections. We describe here the synthesis and biological evaluation of active compounds, 5a-5g, and their precursors (6a, 6b, 6d, and 6e) with flexible bulky hydrophobic groups instead of the rigid polyheterocyclic moieties. In silico docking confirmed the ability of 5a-5g to bind to the active site of influenza A CEN (PDB code: 6FS6) like baloxavir acid, 3. These novel compounds inhibited polymerase complex activity, inhibited virus replication in cells, prevented death in a lethal influenza A virus mouse challenge model, and dramatically lowered viral lung titers. 5a and 5e potently inhibited different influenza genera in vitro. Precursors 6a and 6d demonstrated impressive mouse oral bioavailability with 6a, providing effective in vivo protection. Thus, these novel compounds are potent CEN inhibitors with in vitro and in vivo activity comparable to baloxavir.


Subject(s)
Dibenzothiepins/chemistry , Dibenzothiepins/pharmacology , Endonucleases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Influenza A Virus, H1N1 Subtype/enzymology , Morpholines/chemistry , Morpholines/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Triazines/chemistry , Triazines/pharmacology , Animals , Dibenzothiepins/adverse effects , Dibenzothiepins/pharmacokinetics , Endonucleases/chemistry , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Female , HEK293 Cells , Humans , Influenza A Virus, H1N1 Subtype/drug effects , Mice , Models, Molecular , Morpholines/adverse effects , Morpholines/pharmacokinetics , Protein Conformation , Pyridones/adverse effects , Pyridones/pharmacokinetics , Tissue Distribution , Triazines/adverse effects , Triazines/pharmacokinetics
5.
Mar Drugs ; 18(4)2020 Apr 22.
Article in English | MEDLINE | ID: mdl-32331442

ABSTRACT

The enzymatic depolymerization of fucoidans from brown algae allowed the production of their standardized derivatives with different biological activities. This work aimed to compare the antiviral activities of native (FeF) and modified with enzyme (FeHMP) fucoidans from F. evanescens. The cytotoxicity and antiviral activities of the FeF and FeHMP against herpes viruses (HSV-1, HSV-2), enterovirus (ECHO-1), and human immunodeficiency virus (HIV-1) in Vero and human MT-4 cell lines were examined by methylthiazolyltetrazolium bromide (MTT) and cytopathic effect (CPE) reduction assays, respectively. The efficacy of fucoidans in vivo was evaluated in the outbred mice model of vaginitis caused by HSV-2. We have shown that both FeF and FeHMP significantly inhibited virus-induced CPE in vitro and were more effective against HSV. FeF exhibited antiviral activity against HSV-2 with a selective index (SI) > 40, and FeHMP with SI ˃ 20, when they were added before virus infection or at the early stages of the HSV-2 lifecycle. Furthermore, in vivo studies showed that after intraperitoneal administration (10 mg/kg), both FeF and FeHMP protected mice from lethal intravaginal HSV-2 infection to approximately the same degree (44-56%). Thus, FeF and FeHMP have comparable potency against several DNA and RNA viruses, allowing us to consider the studied fucoidans as promising broad-spectrum antivirals.


Subject(s)
Antiviral Agents/pharmacology , Fucus/chemistry , Polysaccharides/pharmacology , Viruses/drug effects , Animals , Antiviral Agents/isolation & purification , Chlorocebus aethiops , DNA Viruses/drug effects , Disease Models, Animal , Female , Humans , Mice , Polysaccharides/isolation & purification , RNA Viruses/drug effects , Vaginitis/drug therapy , Vaginitis/virology , Vero Cells
6.
Vaccine ; 38(4): 859-867, 2020 01 22.
Article in English | MEDLINE | ID: mdl-31718898

ABSTRACT

Clinical and historical data underscore the ability of influenza viruses to ally with Staphylococcus aureus and predispose the host for secondary bacterial pneumonia, which is a leading cause of influenza-associated mortality. This is fundamental because no vaccine for S. aureus is available and the number of antibiotic-resistant strains is alarmingly rising. Hence, this leaves influenza vaccination the only strategy to prevent postinfluenza staphylococcal infections. In the present work, we assessed the off-target effects of a Tnms42 insect cell-expressed BEI-treated Gag-VLP preparation expressing the HA of A/Puerto Rico/8/1934 (H1N1) in preventing S. aureus superinfection in mice pre-infected with a homologous or heterologous H1N1 viral challenge strain. Our results demonstrate that matched anti-hemagglutinin immunity elicited by a VLP preparation may suffice to prevent morbidity and mortality caused by lethal secondary bacterial infection. This effect was observed even when employing a single low antigen dose of 50 ng HA per animal. However, induction of anti-hemagglutinin immunity alone was not helpful in inhibiting heterologous viral replication and subsequent bacterial infection. Our results indicate the potential of the VLP vaccine approach in terms of immunogenicity but suggest that anti-HA immunity should not be considered as the sole preventive method for combatting influenza and postinfluenza bacterial infections.


Subject(s)
Influenza Vaccines/administration & dosage , Influenza, Human/prevention & control , Staphylococcal Infections/prevention & control , Vaccines, Virus-Like Particle/administration & dosage , Animals , Female , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Humans , Influenza A Virus, H1N1 Subtype/immunology , Influenza Vaccines/immunology , Influenza, Human/complications , Insecta , Mice , Mice, Inbred BALB C , Superinfection/prevention & control , Vaccination , Vaccines, Virus-Like Particle/immunology , Virus Replication/immunology
7.
Vaccines (Basel) ; 7(4)2019 Nov 17.
Article in English | MEDLINE | ID: mdl-31744208

ABSTRACT

: Influenza virus infections pre-dispose an individual to secondary pneumococcal infections, which represent a serious public health concern. Matching influenza vaccination was demonstrated helpful in preventing postinfluenza bacterial infections and associated illnesses in humans. Yet, the impact of influenza hemagglutinin (HA)-specific immunity alone in this dual-infection scenario remains elusive. In the present study, we assessed the protective effect of neutralizing and non-neutralizing anti-hemagglutinin immunity in a BALB/c influenza-pneumococcus superinfection model. Our immunogens were insect cell-expressed hemagglutinin-Gag virus-like particles that had been differentially-treated for the inactivation of bioprocess-related baculovirus impurities. We evaluated the potential of several formulations to restrain the primary infection with vaccine-matched or -mismatched influenza strains and secondary bacterial replication. In addition, we investigated the effect of anti-HA immunity on the interferon status in mouse lungs prior to bacterial challenge. In our experimental setup, neutralizing anti-HA immunity provided significant but incomplete protection from postinfluenza bacterial superinfection, despite effective control of viral replication. In view of this, it was surprising to observe a survival advantage with non-neutralizing adaptive immunity when using a heterologous viral challenge strain. Our findings suggest that both neutralizing and non-neutralizing anti-HA immunity can reduce disease and mortality caused by postinfluenza pneumococcal infections.

8.
J Med Virol ; 91(4): 588-597, 2019 04.
Article in English | MEDLINE | ID: mdl-30431664

ABSTRACT

Antiviral drugs can play a significant role in the control of influenza. Umifenovir (Arbidol) is licensed and widely used in Russia for the prophylaxis and/or treatment of influenza. We evaluated the susceptibility to umifenovir of reference influenza A and B viruses and influenza A viruses isolated from patients in the ARBITR clinical trial in 2012-2014 seasons. Using an MDCK cell-based enzyme-linked immunosorbent assay (ELISA), we showed that the replication of antigenically dominant human influenza A and B viruses was efficiently inhibited by umifenovir. The wild-type А/Perth/265/2009 (H1N1)pdm09, A/Fukui/45/2004 (H3N2), and B/Perth/211/2001 viruses and their oseltamivir-resistant counterparts were susceptible to umifenovir among in vitro laboratory assays. All 18 clinical isolates of influenza A viruses obtained before and during therapy were susceptible to umifenovir with 50% effective concentration (EC 50 ) ranging from 8.4 ± 1.1 to 17.4 ± 5.4 µM. No molecular markers of umifenovir resistance were identified in influenza viruses isolate d from patients at 3, 5, and 7 days after initiation of therapy. None of the viruses isolated before and during umifenovir therapy displayed reduced susceptibility to neuraminidase (NA) inhibitors. Thus, umifenovir is effective against influenza viruses circulating in 2012-2014 seasons, and therapy did not lead to the emergence of drug-resistant variants.


Subject(s)
Antiviral Agents/pharmacology , Indoles/pharmacology , Influenza, Human/virology , Orthomyxoviridae/drug effects , Adolescent , Adult , Aged , Animals , Clinical Trials as Topic , Dogs , Female , Humans , Madin Darby Canine Kidney Cells , Male , Microbial Sensitivity Tests , Middle Aged , Orthomyxoviridae/isolation & purification , Russia , Virus Replication/drug effects , Young Adult
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