Broad Spectrum Antiviral Agent Niclosamide and Its Therapeutic Potential.
Ontology highlight
ABSTRACT:
SUBMITTER: Xu J
PROVIDER: S-EPMC7098069 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacity of squalamine, a cationic amphipathic sterol, to neutralize the negative electrostatic surface charge of intracellular membranes in a way that renders the cell less effective in supporting viral replication. Because squalamine can be readily synthesized and has a known safety profile in man, we believe its potential as a broad-spectrum human antiviral agent should be explored.
| S-EPMC3179074 | biostudies-literature
Project description:Originally developed and commercialized as an antiprotozoal agent, nitazoxanide was later identified as a first-in-class broad-spectrum antiviral drug and has been repurposed for the treatment of influenza. A Phase 2b/3 clinical trial recently published in The Lancet Infectious Diseases found that oral administration of nitazoxanide 600mg twice daily for five days reduced the duration of clinical symptoms and reduced viral shedding compared to placebo in persons with laboratory-confirmed influenza. The same study also suggested a potential benefit for subjects with influenza-like illness who did not have influenza or other documented respiratory viral infection. From a chemical perspective, nitazoxanide is the scaffold for a new class of drugs called thiazolides. These small-molecule drugs target host-regulated processes involved in viral replication. Nitazoxanide is orally bioavailable and safe with extensive post-marketing experience involving more than 75 million adults and children. A new dosage formulation of nitazoxanide is presently undergoing global Phase 3 clinical development for the treatment of influenza. Nitazoxanide inhibits a broad range of influenza A and B viruses including influenza A(pH1N1) and the avian A(H7N9) as well as viruses that are resistant to neuraminidase inhibitors. It is synergistic with neuraminidase inhibitors, and combination therapy with oseltamivir is being studied in humans as part of ongoing Phase 3 clinical development. Nitazoxanide also inhibits the replication of a broad range of other RNA and DNA viruses including respiratory syncytial virus, parainfluenza, coronavirus, rotavirus, norovirus, hepatitis B, hepatitis C, dengue, yellow fever, Japanese encephalitis virus and human immunodeficiency virus in cell culture assays. Clinical trials have indicated a potential role for thiazolides in treating rotavirus and norovirus gastroenteritis and chronic hepatitis B and chronic hepatitis C. Ongoing and future clinical development is focused on viral respiratory infections, viral gastroenteritis and emerging infections such as dengue fever.
| S-EPMC7113776 | biostudies-literature
Project description:We report RNA-seq analysis of Vehicle control, cAIMP, or scleroglucan treated human fibroblasts under uninfected (mock) and Chikungunya virus infected conditions.
2023-02-08 | GSE197744 | GEO
Project description:BACKGROUND:Flaviviruses such as Zika cause sporadic pandemic outbreaks worldwide. There is an urgent need for anti-Zika virus (ZIKV) drugs to prevent mother-to-child transmission of ZIKV, new infections in high-risk populations, and the infection of medical personnel in ZIKV-affected areas. METHODS:Here, we showed that the small molecule 6-deoxyglucose-diphyllin (DGP) exhibited anti-ZIKV activity both in vitro and in vivo. DGP potently blocked ZIKV infection across all human and monkey cell lines tested. DGP also displayed broad-spectrum antiviral activity against other flaviviruses. Remarkably, DGP prevented ZIKV-induced mortality in mice lacking the type I interferon receptor (Ifnar1-/-). Cellular and virological experiments showed that DGP blocked ZIKV at a pre-fusion step or during fusion, which prevented the delivery of viral contents into the cytosol of the target cell. Mechanistic studies revealed that DGP prevented the acidification of endosomal/lysosomal compartments in target cells, thus inhibiting ZIKV fusion with cellular membranes and infection. FINDINGS:These investigations revealed that DGP inhibits ZIKV infection in vitro and in vivo. INTERPRETATION:The small molecule DGP has great potential for preclinical studies and the ability to inhibit ZIKV infection in humans.
| S-EPMC6796538 | biostudies-literature
Project description:Here we report the structure-activity relationship (SAR) investigations of QL-XII-47 (QL47), a compound that possesses broad-spectrum antiviral activity against dengue virus and other RNA viruses. A medicinal chemistry campaign initiated from QL47, a previously reported covalent BTK inhibitor, to derive YKL-04-085, which is devoid of any kinase activity when screened against a panel of 468 kinases and with improved pharmacokinetic properties. Both QL47 and YKL-04-085 are potent inhibitors of viral translation and exhibit cellular antiviral activity at 35-fold lower concentrations relative to inhibition of host-cell proliferation.
| S-EPMC5346993 | biostudies-literature
Project description:RNA viruses continue to remain a clear and present threat for potential pandemics due to their rapid evolution. To mitigate their impact, we urgently require antiviral agents that can inhibit multiple families of disease-causing viruses, such as arthropod-borne and respiratory pathogens. Potentiating host antiviral pathways can prevent or limit viral infections before escalating into a major outbreak. Therefore, it is critical to identify broad-spectrum antiviral agents. We have tested a small library of innate immune agonists targeting pathogen recognition receptors, including TLRs, STING, NOD, Dectin and cytosolic DNA or RNA sensors. We observed that TLR3, STING, TLR8 and Dectin-1 ligands inhibited arboviruses, Chikungunya virus (CHIKV), West Nile virus (WNV) and Zika virus, to varying degrees. Cyclic dinucleotide (CDN) STING agonists, such as cAIMP, diABZI, and 2',3'-cGAMP, and Dectin-1 agonist scleroglucan, demonstrated the most potent, broad-spectrum antiviral function. Comparative transcriptome analysis revealed that CHIKV-infected cells had larger number of differentially expressed genes than of WNV and ZIKV. Furthermore, gene expression analysis showed that cAIMP treatment rescued cells from CHIKV-induced dysregulation of cell repair, immune, and metabolic pathways. In addition, cAIMP provided protection against CHIKV in a CHIKV-arthritis mouse model. Cardioprotective effects of synthetic STING ligands against CHIKV, WNV, SARS-CoV-2 and enterovirus D68 (EV-D68) infections were demonstrated using human cardiomyocytes. Interestingly, the direct-acting antiviral drug remdesivir, a nucleoside analogue, was not effective against CHIKV and WNV, but exhibited potent antiviral effects against SARS-CoV-2, RSV (respiratory syncytial virus), and EV-D68. Our study identifies broad-spectrum antivirals effective against multiple families of pandemic potential RNA viruses, which can be rapidly deployed to prevent or mitigate future pandemics.
| S-EPMC9882367 | biostudies-literature
Project description:Broad-spectrum antiviral therapies hold promise as a first-line defense against emerging viruses by blunting illness severity and spread until vaccines and virus-specific antivirals are developed. The nucleobase favipiravir, often discussed as a broad-spectrum inhibitor, was not effective in recent clinical trials involving patients infected with Ebola virus or SARS-CoV-2. A drawback of favipiravir use is its rapid clearance before conversion to its active nucleoside-5'-triphosphate form. In this work, we report a synergistic reduction of flavivirus (dengue, Zika), orthomyxovirus (influenza A), and coronavirus (HCoV-OC43 and SARS-CoV-2) replication when the nucleobases favipiravir or T-1105 were combined with the antimetabolite 6-methylmercaptopurine riboside (6MMPr). The 6MMPr/T-1105 combination increased the C-U and G-A mutation frequency compared to treatment with T-1105 or 6MMPr alone. A further analysis revealed that the 6MMPr/T-1105 co-treatment reduced cellular purine nucleotide triphosphate synthesis and increased conversion of the antiviral nucleobase to its nucleoside-5'-monophosphate, -diphosphate, and -triphosphate forms. The 6MMPr co-treatment specifically increased production of the active antiviral form of the nucleobases (but not corresponding nucleosides) while also reducing levels of competing cellular NTPs to produce the synergistic effect. This in-depth work establishes a foundation for development of small molecules as possible co-treatments with nucleobases like favipiravir in response to emerging RNA virus infections.
| S-EPMC8705664 | biostudies-literature
Project description:Lately, nitrogenous heterocyclic antivirals, such as nucleoside-like compounds, oxadiazoles, thiadiazoles, triazoles, quinolines, and isoquinolines, topped the therapeutic scene as promising agents of choice for the treatment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and their accompanying ailment, the coronavirus disease 2019 (COVID-19). At the same time, the continuous emergence of new strains of SARS-CoV-2, like the Omicron variant and its multiple sublineages, resulted in a new defiance in the enduring COVID-19 battle. Ensitrelvir (S-217622) is a newly discovered orally active noncovalent nonpeptidic agent with potential strong broad-spectrum anticoronaviral activities, exhibiting promising nanomolar potencies against the different SARS-CoV-2 variants. S-217622 effectively and nonspecifically hits the main protease (Mpro) enzyme of a broad scope of coronaviruses. Herein, in the present computational/biological study, we tried to extend these previous findings to prove the universal activities of this investigational agent against any coronavirus, irrespective of its type, through synchronously acting on most of its main unchanged replication enzymes/proteins, including (in addition to the Mpro), e.g., the highly conserved RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN). Biochemical evaluation proved, using the in vitro anti-RdRp/ExoN bioassay, that S-217622 can potently inhibit the replication of coronaviruses, including the new virulent strains of SARS-CoV-2, with extremely minute in vitro anti-RdRp and anti-RdRp/ExoN half-maximal effective concentration (EC50) values of 0.17 and 0.27 μM, respectively, transcending the anti-COVID-19 drug molnupiravir. The preliminary in silico results greatly supported these biochemical results, proposing that the S-217622 molecule strongly and stabilizingly strikes the key catalytic pockets of the SARS-CoV-2 RdRp's and ExoN's principal active sites predictably via the nucleoside analogism mode of anti-RNA action (since the S-217622 molecule can be considered as a uridine analog). Moreover, the idealistic druglikeness and pharmacokinetic characteristics of S-217622 make it ready for pharmaceutical formulation with the expected very good clinical behavior as a drug for the infections caused by coronaviruses, e.g., COVID-19. To cut it short, the current critical findings of this extension work significantly potentiate and extend the S-217622's previous in vitro/in vivo (preclinical) results since they showed that the striking inhibitory activities of this novel anti-SARS-CoV-2 agent on the Mpro could be extended to other replication enzymes like RdRp and ExoN, unveiling the possible universal use of the compound against the next versions of the virus (i.e., disclosing the nonspecific anticoronaviral properties of this compound against almost any coronavirus strain), e.g., SARS-CoV-3, and encouraging us to rapidly start the compound's vast clinical anti-COVID-19 evaluations.
| S-EPMC9897045 | biostudies-literature
Project description:Currently there are relatively few antiviral therapeutics, and most which do exist are highly pathogen-specific or have other disadvantages. We have developed a new broad-spectrum antiviral approach, dubbed Double-stranded RNA (dsRNA) Activated Caspase Oligomerizer (DRACO) that selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have created DRACOs and shown that they are nontoxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arenaviruses, Guama bunyavirus, and H1N1 influenza. We have also demonstrated that DRACOs can rescue mice challenged with H1N1 influenza. DRACOs have the potential to be effective therapeutics or prophylactics for numerous clinical and priority viruses, due to the broad-spectrum sensitivity of the dsRNA detection domain, the potent activity of the apoptosis induction domain, and the novel direct linkage between the two which viruses have never encountered.
| S-EPMC3144912 | biostudies-literature
Project description:FDA approved for parasitic indications, the small molecule ivermectin has been the focus of growing attention in the last 8 years due to its potential as an antiviral. We first identified ivermectin in a high throughput compound library screen as an agent potently able to inhibit recognition of the nuclear localizing Human Immunodeficiency Virus-1 (HIV-1) integrase protein by the host importin (IMP) α/β1 heterodimer, and recently demonstrated its ability to bind directly to IMPα to cause conformational changes that prevent its function in nuclear import of key viral as well as host proteins. Cell culture experiments have shown robust antiviral action towards a whole range of viruses, including HIV-1, dengue, Zika and West Nile Virus, Venezuelan equine encephalitis virus, Chikungunya, pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19). Close to 70 clinical trials are currently in progress worldwide for SARS-CoV-2. Although few of these studies have been completed, the results that are available, as well as those from observational/retrospective studies, indicate clinical benefit. Here we discuss the case for ivermectin as a host-directed broad-spectrum antiviral agent, including for SARS-CoV-2.
| S-EPMC7577703 | biostudies-literature