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International Journal of Molecular... Jul 2023Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical "magic shotgun". Until 2007, APR was widely used as an antithrombotic and... (Review)
Review
Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical "magic shotgun". Until 2007, APR was widely used as an antithrombotic and anti-inflammatory drug in cardiac and noncardiac surgeries for reduction of bleeding and thus limiting the need for blood transfusion. The ability of APR to inhibit proteolytic activation of some viruses leads to its use as an antiviral drug for the prevention and treatment of acute respiratory virus infections. However, due to incompetent interpretation of several clinical trials followed by incredible controversy in the literature, the usage of APR was nearly stopped for a decade worldwide. In 2015-2020, after re-analysis of these clinical trials' data the restrictions in APR usage were lifted worldwide. This review discusses antiviral mechanisms of APR action and summarizes current knowledge and prospective regarding the use of APR treatment for diseases caused by RNA-containing viruses, including influenza and SARS-CoV-2 viruses, or as a part of combination antiviral treatment.
Topics: Humans; Aprotinin; SARS-CoV-2; Prospective Studies; COVID-19; Antiviral Agents; Respiration Disorders
PubMed: 37446350
DOI: 10.3390/ijms241311173 -
Nature Communications Jul 2023Nirmatrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro), is clinically useful against infection with SARS-CoV-2 including its omicron...
Nirmatrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro), is clinically useful against infection with SARS-CoV-2 including its omicron variants. Since most omicron subvariants have reduced sensitivity to many monoclonal antibody therapies, potential SARS-CoV-2 resistance to nirmatrelvir is a major public health concern. Several amino acid substitutions have been identified as being responsible for reduced susceptibility to nirmatrelvir. Among them, we selected L50F/E166V and L50F/E166A/L167F in the 3CLpro because these combinations of substitutions are unlikely to affect virus fitness. We prepared and characterized delta variants possessing Nsp5-L50F/E166V and Nsp5-L50F/E166A/L167F. Both mutant viruses showed decreased susceptibility to nirmatrelvir and their growth in VeroE6/TMPRSS2 cells was delayed. Both mutant viruses showed attenuated phenotypes in a male hamster infection model, maintained airborne transmissibility, and were outcompeted by wild-type virus in co-infection experiments in the absence of nirmatrelvir, but less so in the presence of the drug. These results suggest that viruses possessing Nsp5-L50F/E166V and Nsp5-L50F/E166A/L167F do not become dominant in nature. However, it is important to closely monitor the emergence of nirmatrelvir-resistant SARS-CoV-2 variants because resistant viruses with additional compensatory mutations could emerge, outcompete the wild-type virus, and become dominant.
Topics: Male; Animals; Cricetinae; COVID-19; SARS-CoV-2; Amino Acid Substitution; Antiviral Agents; Lactams; Leucine; Nitriles
PubMed: 37402789
DOI: 10.1038/s41467-023-39704-x -
Journal of Advanced Research Feb 2024Enterovirus A71 (EV-A71) is capable of causing hand, foot and mouth disease (HFMD), which may lead to neurological sequelae and even death. As EV-A71 is resistant to... (Review)
Review
BACKGROUND
Enterovirus A71 (EV-A71) is capable of causing hand, foot and mouth disease (HFMD), which may lead to neurological sequelae and even death. As EV-A71 is resistant to environmental changes and mutates easily, there is still a lack of effective treatments or globally available vaccines.
AIM OF REVIEW
For more than 50 years since the HFMD epidemic, related drug research has been conducted. Progress in this area can promote the further application of existing potential drugs and develop more efficient and safe antiviral drugs, and provide useful reference for protecting the younger generation and maintaining public health security.
KEY SCIENTIFIC CONCEPTS OF REVIEW
At present, researchers have identified hundreds of EV-A71 inhibitors based on screening repurposed drugs, targeted structural design, and rational modification of previously effective drugs as the main development strategies. This review systematically introduces the current potential drugs to inhibit EV-A71 infection, including viral inhibitors targeting key sites such as the viral capsid, RNA-dependent RNA polymerase (RdRp), 2C protein, internal ribosome entry site (IRES), 3C proteinase (3C), and 2A proteinase (2A), starting from each stage of the viral life cycle. Meanwhile, the progress of host-targeting antiviral drugs and their development are summarized in terms of regulating host immunity, inhibiting autophagy or apoptosis, and regulating the cellular redox environment. In addition, the current clinical methods for the prevention and treatment of HFMD are summarized and discussed with the aim of providing support and recommendations for the treatment of enterovirus infections including EV-A71.
Topics: Humans; Enterovirus; Enterovirus A, Human; Enterovirus Infections; Drug Development; Antiviral Agents
PubMed: 37001813
DOI: 10.1016/j.jare.2023.03.007 -
European Journal of Medicinal Chemistry Nov 2023Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) identified in 2003 infected ∼8000 people in 26 countries with 800 deaths, which was soon contained... (Review)
Review
Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) identified in 2003 infected ∼8000 people in 26 countries with 800 deaths, which was soon contained and eradicated by syndromic surveillance and enhanced quarantine. A closely related coronavirus SARS-CoV-2, the causative agent of COVID-19 identified in 2019, has been dramatically more contagious and catastrophic. It has infected and caused various flu-like symptoms of billions of people in >200 countries, including >6 million people died of or with the virus. Despite the availability of several vaccines and antiviral drugs against SARS-CoV-2, finding new therapeutics is needed because of viral evolution and a possible emerging coronavirus in the future. The main protease (M) of these coronaviruses plays important roles in their life cycle and is essential for the viral replication. This article represents a comprehensive review of the function, structure and inhibition of SARS-CoV and -CoV-2 M, including structure-activity relationships, protein-inhibitor interactions and clinical trial status.
Topics: Humans; Antiviral Agents; COVID-19; Peptide Hydrolases; SARS-CoV-2; Severe acute respiratory syndrome-related coronavirus; Clinical Trials as Topic
PubMed: 37659195
DOI: 10.1016/j.ejmech.2023.115772 -
Journal of the Formosan Medical... Jan 2024The coronavirus disease 2019 (COVID-19) pandemic has reached a turning point. The non-pharmaceutical interventions for preventing COVID-19 are lifting. Vaccination... (Review)
Review
The coronavirus disease 2019 (COVID-19) pandemic has reached a turning point. The non-pharmaceutical interventions for preventing COVID-19 are lifting. Vaccination uptake is increasing in general, but this strategy is continuously challenged by the rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of note, the Omicron subvariants spread globally for at least one year, and the most recently developed subvariants show strong immune evasion to preexisting immunity, either from previous infection, vaccination or both. Therefore, early and appropriate antiviral agents to treat patients at risk for severe COVID-19 or death is crucial to decrease morbidities and mortalities, to restore the healthcare capacities and to facilitate a return to the new normal. Current antiviral therapy for COVID-19 consist of neutralizing monoclonal antibodies (mAbs) and direct antiviral agents. Each agent has been proved for early ambulatory treatment of COIVD-19, but suffer from variable effectiveness and limitations due to patients' comorbidities, drug properties, or antiviral resistance. Besides, some specific mAbs are indicated for prophylaxis of COVID-19 before or after close contact with confirmed COVID-19 patients. This review article summarizes the evidence and unmet needs of the currently available antiviral agents for management of COVID-19 in the context of the Omicron subvariants.
Topics: Humans; COVID-19; SARS-CoV-2; Antibodies, Monoclonal; Drug Resistance, Viral; Antiviral Agents
PubMed: 37661527
DOI: 10.1016/j.jfma.2023.08.029 -
International Journal of Molecular... Sep 2023Studies on virus-host interactions are of high significance for a number of reasons [...].
Studies on virus-host interactions are of high significance for a number of reasons [...].
Topics: Antiviral Agents; Host-Pathogen Interactions; Virus Replication
PubMed: 37833992
DOI: 10.3390/ijms241914555 -
MBio Aug 2023Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as the causative agent of the recent COVID-19 pandemic, continues representing one of the main health... (Review)
Review
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as the causative agent of the recent COVID-19 pandemic, continues representing one of the main health concerns worldwide. Autophagy, in addition to its role in cellular homeostasis and metabolism, plays an important part for the host antiviral immunity. However, viruses including SARS-CoV-2 have evolved diverse mechanisms to not only overcome autophagy's antiviral pressure but also manipulate its machinery in order to enhance viral replication and propagation. Here, we discuss our current knowledge on the impact that autophagy exerts on SARS-CoV-2 replication, as well as the different counteracting measures that this virus has developed to manipulate autophagy's complex machinery. Some of the elements regarding this interplay may become future therapeutic targets in the fight against SARS-CoV-2.
Topics: Humans; SARS-CoV-2; COVID-19; Pandemics; Antiviral Agents; Autophagy
PubMed: 37436071
DOI: 10.1128/mbio.01020-23 -
Immunity, Inflammation and Disease Aug 2023High morbidity and mortality of influenza virus infection have made it become one of the most lethal diseases threatening public health; the lack of drugs with strong... (Review)
Review
BACKGROUND
High morbidity and mortality of influenza virus infection have made it become one of the most lethal diseases threatening public health; the lack of drugs with strong antiviral activity against virus strains exacerbates the problem.
METHODS
Two independent researchers searched relevant studies using Embase, PubMed, Web of Science, Google Scholar, and MEDLINE databases from its inception to December 2022.
RESULTS
Based on the different antiviral mechanisms, current antiviral strategies can be mainly classified into virus-targeting approaches such as neuraminidase inhibitors, matrix protein 2 ion channel inhibitors, polymerase acidic protein inhibitors and other host-targeting antivirals. However, highly viral gene mutation has underscored the necessity of novel antiviral drug development. Arbidol (ARB) is a Russian-made indole-derivative small molecule licensed in Russia and China for the prevention and treatment of influenza and other respiratory viral infections. ARB also has inhibitory effects on many other viruses such as severe acute respiratory syndrome coronavirus 2, Coxsackie virus, respiratory syncytial virus, Hantaan virus, herpes simplex virus, and hepatitis B and C viruses. ARB is a promising drug which can not only exert activity against virus at different steps of virus replication cycle, but also directly target on hosts before infection to prevent virus invasion.
CONCLUSION
ARB is a broad-spectrum antiviral drug that inhibits several viruses in vivo and in vitro, with high safety profile and low resistance; the antiviral mechanisms of ARB deserve to be further explored and more high-quality clinical studies are required to establish the efficacy and safety of ARB.
Topics: Humans; Antiviral Agents; Influenza, Human; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; COVID-19
PubMed: 37647451
DOI: 10.1002/iid3.984 -
Journal of Molecular Biology Feb 2024Viral infections pose a significant health risk worldwide. There is a pressing need for more effective antiviral drugs to combat emerging novel viruses and the... (Review)
Review
Viral infections pose a significant health risk worldwide. There is a pressing need for more effective antiviral drugs to combat emerging novel viruses and the reemergence of previously controlled viruses. Biomolecular condensates are crucial for viral replication and are promising targets for novel antiviral therapies. Herein, we review the role of biomolecular condensates in the viral replication cycle and discuss novel strategies to leverage condensate biology for antiviral drug discovery. Biomolecular condensates may also provide an opportunity to develop antivirals that are broad-spectrum or less prone to acquired drug resistance.
Topics: Humans; Antiviral Agents; Biomolecular Condensates; Virus Diseases; Virus Replication; Drug Discovery
PubMed: 38061626
DOI: 10.1016/j.jmb.2023.168380 -
Journal of Medical Virology Aug 2023Intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in hepatitis B virus (HBV) infection, cellular responses, antiviral, and...
Intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in hepatitis B virus (HBV) infection, cellular responses, antiviral, and immunomodulator responses. Twelve ICOs generated from liver resections and biopsies were assessed for metabolic markers and functional HBV entry receptor expression throughout differentiation. Structural changes relevant to HBV infection were characterized using histology, confocal, and electron microscopy examinations. Optimal ICO culture conditions for HBV infection using HepAD38 (genotype D) and plasma derived HBV (genotype B & C) were described. HBV infection was confirmed using HBcAg immunostaining, qRT-PCR (RNA, cccDNA, extracellular DNA), and ELISA (HBsAg and HBeAg). Drug response to antiviral and immunosuppressive agent, and cellular responses (interferon-stimulated genes [ISG]) to interferon-α and viral mimic (PolyI:C) were assessed. ICOs underwent metabolic and structural remodeling following differentiation. Optimal HBV infection was achieved in well-differentiated ICOs using spinoculation, with time and donor dependent increase in HBV RNA, cccDNA, extracellular DNA, HBeAg, and HBsAg. Donor dependent drug-responsiveness to entry inhibitor and JAK inhibitor was observed. Despite having a robust ISG response to interferon-α and PolyI:C, HBV infection in ICOs did not upregulate ISGs. Human ICOs support HBV infection and replication with donor dependent variation in viral dynamics and cellular responses. These features can be utilized for development of personalized drug testing platform for antivirals.
Topics: Humans; Hepatitis B virus; Hepatitis B Surface Antigens; Hepatitis B e Antigens; Hepatitis B, Chronic; Hepatitis B; Antiviral Agents; Interferon-alpha; Organoids; RNA; DNA, Viral; Liver
PubMed: 37503549
DOI: 10.1002/jmv.28975