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The Journal of Biological Chemistry Nov 2023The emergence of severe acute respiratory syndrome coronavirus 2, the causative agent of coronavirus disease 2019, has resulted in the largest pandemic in recent...
The emergence of severe acute respiratory syndrome coronavirus 2, the causative agent of coronavirus disease 2019, has resulted in the largest pandemic in recent history. Current therapeutic strategies to mitigate this disease have focused on the development of vaccines and on drugs that inhibit the viral 3CL protease or RNA-dependent RNA polymerase enzymes. A less-explored and potentially complementary drug target is Nsp15, a uracil-specific RNA endonuclease that shields coronaviruses and other nidoviruses from mammalian innate immune defenses. Here, we perform a high-throughput screen of over 100,000 small molecules to identify Nsp15 inhibitors. We characterize the potency, mechanism, selectivity, and predicted binding mode of five lead compounds. We show that one of these, IPA-3, is an irreversible inhibitor that might act via covalent modification of Cys residues within Nsp15. Moreover, we demonstrate that three of these inhibitors (hexachlorophene, IPA-3, and CID5675221) block severe acute respiratory syndrome coronavirus 2 replication in cells at subtoxic doses. This study provides a pipeline for the identification of Nsp15 inhibitors and pinpoints lead compounds for further development against coronavirus disease 2019 and related coronavirus infections.
Topics: Antiviral Agents; Endoribonucleases; SARS-CoV-2; Viral Nonstructural Proteins; Virus Replication
PubMed: 37832873
DOI: 10.1016/j.jbc.2023.105341 -
Virus Research Jan 2024African Swine Fever Virus (ASFV) infection causes an acute and highly contagious disease in swine, resulting in significant economic losses and societal harm worldwide....
African Swine Fever Virus (ASFV) infection causes an acute and highly contagious disease in swine, resulting in significant economic losses and societal harm worldwide. Currently, there are no effective vaccines or antiviral drugs available for ASFV. Tetrandrine (TET) is extracted from the traditional Chinese herb Stephania tetrandrae, possesses diverse biological functions such as anti-inflammatory, anti-tumor, and antiviral activities. The study comprehensively evaluated the anti-ASFV effect of TET and validated it through biological assays. The dose-dependent inhibition of TET against ASFV was confirmed and a novel mechanism of TET's anti-ASFV activity was elucidated. TET effectively inhibits ASFV during internalization by blocking macropinocytosis through the inhibition of the PI3K/Akt pathway. The specific inhibitor LY294002, targeting the PI3K/Akt pathway, exhibits similar antiviral activity against ASFV as TET. Furthermore, the inhibitory effect of TET against other viruses such as Lumpy Skin Disease Virus (LSDV) and Porcine Epidemic Diarrhea Virus (PEDV) was also identified. Our findings suggest that TET effectively inhibits ASFV and reveal the potential for broad-spectrum antiviral drugs targeting the PI3K/Akt pathway.
Topics: Animals; African Swine Fever; African Swine Fever Virus; Antiviral Agents; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Swine; Benzylisoquinolines; Virus Internalization
PubMed: 37923171
DOI: 10.1016/j.virusres.2023.199258 -
MBio Oct 2023Studying the co-evolution between viruses and humans is important for understanding why we are what we are now as well as for developing future antiviral drugs. Here we...
Studying the co-evolution between viruses and humans is important for understanding why we are what we are now as well as for developing future antiviral drugs. Here we pinned down an evolutionary arms race between retroviruses and mammalian hosts at the molecular level by identifying the antagonism between a host antiviral restriction factor PSGL-1 and viral accessory proteins. We show that this antagonism is conserved from mouse to human and from mouse retrovirus to HIV. Further studying this antagonism might provide opportunities for developing new antiviral therapies.
Topics: Humans; Mice; Animals; Viral Regulatory and Accessory Proteins; Retroviridae; Mammals; Antiviral Agents
PubMed: 37787515
DOI: 10.1128/mbio.00387-23 -
European Journal of Medicinal Chemistry Sep 2023The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The main protease (M) of... (Review)
Review
The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The main protease (M) of SARS-CoV-2 plays a central role in viral replication and transcription and represents an attractive drug target for fighting COVID-19. Many SARS-CoV-2 M inhibitors have been reported, including covalent and noncovalent inhibitors. The SARS-CoV-2 M inhibitor PF-07321332 (Nirmatrelvir) designed by Pfizer has been put on the market. This paper briefly introduces the structural characteristics of SARS-CoV-2 M and summarizes the research progress of SARS-CoV-2 M inhibitors from the aspects of drug repurposing and drug design. These information will provide a basis for the drug development of treating the infection of SARS-CoV-2 and even other coronaviruses in the future.
Topics: Humans; COVID-19; SARS-CoV-2; Antiviral Agents; Protease Inhibitors; Viral Nonstructural Proteins; Molecular Docking Simulation
PubMed: 37244162
DOI: 10.1016/j.ejmech.2023.115491 -
Frontiers in Cellular and Infection... 2023
Topics: Antiviral Agents; Immunity, Innate; Research; Viruses
PubMed: 37621872
DOI: 10.3389/fcimb.2023.1268363 -
Biomedicine & Pharmacotherapy =... Dec 2023Natural products are a rich source of bioactive molecules that have potential pharmacotherapeutic applications. In this study, we focused on Artemisia annua (A. annua)...
Natural products are a rich source of bioactive molecules that have potential pharmacotherapeutic applications. In this study, we focused on Artemisia annua (A. annua) and its enriched extracts which were biologically evaluated in vitro as virucidal, antiviral, and antioxidant agents, with a potential application against the COVID-19 infection. The crude extract showed virucidal, antiviral and antioxidant effects in concentrations that did not affect cell viability. Scopoletin, arteannuin B and artemisinic acid (single fractions isolated from A. annua) exerted a considerable virucidal and antiviral effect in vitro starting from a concentration of 50 µg/mL. Data from Surface Plasmon Resonance (SPR) showed that the inhibition of the viral infection was due to the interaction of these compounds with the 3CLpro and Spike proteins of SARS-CoV-2, suggesting that the main interaction of compounds may interfere with the viral pathways during the insertion and the replication process. The present study suggests that natural extract of A. annua and its components could have a key role as antioxidants and antiviral agents and support the fight against SARS-CoV-2 variants and other possible emerging Coronaviruses.
Topics: SARS-CoV-2; Antioxidants; Artemisia annua; Plant Extracts; COVID-19; Antiviral Agents
PubMed: 37832410
DOI: 10.1016/j.biopha.2023.115682 -
Peptides Aug 2023Viral epidemics are occurring frequently, and the COVID-19 viral pandemic has resulted in at least 6.5 million deaths worldwide. Although antiviral therapeutics are... (Review)
Review
Viral epidemics are occurring frequently, and the COVID-19 viral pandemic has resulted in at least 6.5 million deaths worldwide. Although antiviral therapeutics are available, these may not have sufficient effect. The emergence of resistant or novel viruses requires new therapies. Cationic antimicrobial peptides are agents of the innate immune system that may offer a promising solution to viral infections. These peptides are gaining attention as possible therapies for viral infections or for use as prophylactic agents to prevent viral spread. This narrative review examines antiviral peptides, their structural features, and mechanism of activity. A total of 156 cationic antiviral peptides were examined for information of their mechanism of action against both enveloped and non-enveloped viruses. Antiviral peptides can be isolated from various natural sources or can be generated synthetically. The latter tend to be more specific and effective and can be made to have a broad spectrum of activity with minimal side effects. Their unique properties of being positively charged and amphipathic enable their main mode of action which is to target and disrupt viral lipid envelopes, thereby inhibiting viral entry and replication. This review offers a comprehensive summary of the current understanding of antiviral peptides, which could potentially aid in the design and creation of novel antiviral medications.
Topics: Humans; Antiviral Agents; Antimicrobial Cationic Peptides; COVID-19; Viruses; Virus Diseases
PubMed: 37172781
DOI: 10.1016/j.peptides.2023.171024 -
Journal of Hepatology Feb 2024Chronic co-infection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. To date, no treatment induces efficient viral clearance, and a better...
BACKGROUND & AIMS
Chronic co-infection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. To date, no treatment induces efficient viral clearance, and a better characterization of virus-host interactions is required to develop new therapeutic strategies.
METHODS
Using loss-of-function strategies, we validated the unexpected proviral activity of Janus kinase 1 (JAK1) - a key player in innate immunity - in the HDV life cycle and determined its mechanism of action on HDV through various functional analyses including co-immunoprecipitation assays.
RESULTS
We confirmed the key role of JAK1 kinase activity in HDV infection. Moreover, our results suggest that JAK1 inhibition is associated with a modulation of ERK1/2 activation and S-HDAg phosphorylation, which is crucial for viral replication. Finally, we showed that FDA-approved JAK1-specific inhibitors are efficient antivirals in relevant in vitro models including primary human hepatocytes.
CONCLUSIONS
Taken together, we uncovered JAK1 as a key host factor for HDV replication and a potential target for new antiviral treatment.
IMPACT AND IMPLICATIONS
Chronic hepatitis D is the most aggressive form of chronic viral hepatitis. As no curative treatment is currently available, new therapeutic strategies based on host-targeting agents are urgently needed. Here, using loss-of-function strategies, we uncover an unexpected interaction between JAK1, a major player in the innate antiviral response, and HDV infection. We demonstrated that JAK1 kinase activity is crucial for both the phosphorylation of the delta antigen and the replication of the virus. By demonstrating the antiviral potential of several FDA-approved JAK1 inhibitors, our results could pave the way for the development of innovative therapeutic strategies to tackle this global health threat.
Topics: Humans; Hepatitis Delta Virus; Janus Kinase 1; Hepatitis B virus; Hepatitis D, Chronic; Antiviral Agents; Virus Replication
PubMed: 37925078
DOI: 10.1016/j.jhep.2023.10.030 -
Viruses Aug 2023Hepatitis D virus (HDV) is a defective RNA virus with a negative-strand RNA genome encompassing less than 1700 nucleotides. The HDV genome encodes only for one protein,... (Review)
Review
Hepatitis D virus (HDV) is a defective RNA virus with a negative-strand RNA genome encompassing less than 1700 nucleotides. The HDV genome encodes only for one protein, the hepatitis delta antigen (HDAg), which exists in two forms acting as nucleoproteins. HDV depends on the envelope proteins of the hepatitis B virus as a helper virus for packaging its ribonucleoprotein complex (RNP). HDV is considered the causative agent for the most severe form of viral hepatitis leading to liver fibrosis/cirrhosis and hepatocellular carcinoma. Many steps of the life cycle of HDV are still enigmatic. This review gives an overview of the complete life cycle of HDV and identifies gaps in knowledge. The focus is on the description of cellular factors being involved in the life cycle of HDV and the deregulation of cellular pathways by HDV with respect to their relevance for viral replication, morphogenesis and HDV-associated pathogenesis. Moreover, recent progress in antiviral strategies targeting cellular structures is summarized in this article.
Topics: Animals; Hepatitis Delta Virus; Hepatitis delta Antigens; Antiviral Agents; Life Cycle Stages; Liver Cirrhosis; Liver Neoplasms
PubMed: 37632029
DOI: 10.3390/v15081687 -
Molecules (Basel, Switzerland) May 2024The FDA has approved several drugs based on the fluorinated nucleoside pharmacophore, and numerous drugs are currently in clinical trials. Fluorine-containing... (Review)
Review
The FDA has approved several drugs based on the fluorinated nucleoside pharmacophore, and numerous drugs are currently in clinical trials. Fluorine-containing nucleos(t)ides offer significant antiviral and anticancer activity. The insertion of a fluorine atom, either in the base or sugar of nucleos(t)ides, alters its electronic and steric parameters and transforms the lipophilicity, pharmacodynamic, and pharmacokinetic properties of these moieties. The fluorine atom restricts the oxidative metabolism of drugs and provides enzymatic metabolic stability towards the glycosidic bond of the nucleos(t)ide. The incorporation of fluorine also demonstrates additional hydrogen bonding interactions in receptors with enhanced biological profiles. The present article discusses the synthetic methodology and antiviral activities of FDA-approved drugs and ongoing fluoro-containing nucleos(t)ide drug candidates in clinical trials.
Topics: Humans; Antiviral Agents; Fluorine; Halogenation; Nucleosides; Nucleotides; Clinical Trials as Topic
PubMed: 38792251
DOI: 10.3390/molecules29102390