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European Journal of Medicinal Chemistry Oct 2020The new virus of the of β-Coronaviruses genus, SARS-CoV-2, is the causative agent of coronavirus disease-2019 (COVID-19) and is winning a proverbial chess match against... (Review)
Review
The new virus of the of β-Coronaviruses genus, SARS-CoV-2, is the causative agent of coronavirus disease-2019 (COVID-19) and is winning a proverbial chess match against all players simultaneous, including physicians, clinicians, pathologists, doctors, scientists, economists, athletes and politicians. The COVID-19 outbreak has seriously threatened public health, killing the most vulnerable persons and causing general panic. To stop this disease, effective remedies (i.e., drugs, vaccines, personal protection elements, etc.) are urgently required. Unfortunately, no registered specific therapies (including antiviral therapies, immune-modulating agents and vaccines) are currently available to treat coronavirus infections, highlighting an urgent need for therapeutics targeting SARS-CoV-2. In this work, fourteen existing small molecule drugs or/and experimental drugs selected by experts and examined from the point of view of bioavailability via the Lipinski-Veber rules and assessment of their physicochemical descriptors. The aim of this study is to discover selected pattern similarities and peculiar characteristics that could be useful for antiviral drug optimization, drug combination or new antiviral agent design.
Topics: Animals; Antiviral Agents; Betacoronavirus; Biological Availability; COVID-19; COVID-19 Vaccines; Coronavirus Infections; Drug Combinations; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2; Viral Vaccines; COVID-19 Drug Treatment
PubMed: 32693298
DOI: 10.1016/j.ejmech.2020.112647 -
Medicina (Kaunas, Lithuania) Sep 2022Background and objectives: The COVID-19 pandemic continues worldwide, and there is no effective treatment to treat it. Chinese medicine is considered the recommended...
Background and objectives: The COVID-19 pandemic continues worldwide, and there is no effective treatment to treat it. Chinese medicine is considered the recommended treatment for COVID-19 in China. This study aimed to examine the effectiveness of tetrandrine in treating COVID-19, which is originally derived from Chinese medicine. Materials and Methods: A total of 60 patients, categorized into three types (mild, moderate, severe), from Daye Hospital of Chinese Medicine with a diagnosis of COVID-19 were included in this study. Demographics, medical history, treatment, and results were collected. We defined two main groups according to the clinical outcome between improvement and recovery. All underlying factors including clinical outcomes were assessed in the total number of COVID-19 patients and moderate-type patients. Results: In a total of 60 patients, there were significant differences in the clinical outcome underlying treatment with antibiotics, tetrandrine, and arbidol (p < 0.05). When the comparison was limited to the moderate type, treatment with tetrandrine further increased recovery rate (p = 0.007). However, the difference disappeared, and no association was indicated between the clinical outcome and the treatment with and without antibiotic (p = 0.224) and arbidol (p = 0.318) in the moderate-type patients. In all-type and moderate-type patients, tetrandrine improved the rate of improvement in cough and fatigue on day 7 (p < 0.05). Conclusions: Tetrandrine may improve clinical outcome in COVID-19 patientsand could be a promising potential natural antiviral agent for the prevention and treatment of COVID-19.
Topics: Anti-Bacterial Agents; Antiviral Agents; Benzylisoquinolines; Humans; Pandemics; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 36143871
DOI: 10.3390/medicina58091194 -
Cell Cycle (Georgetown, Tex.) Jan 2021To date, proposed therapies and antiviral drugs have been failed to cure coronavirus disease 2019 (COVID-19) patients. However, at least two drug companies have applied... (Review)
Review
To date, proposed therapies and antiviral drugs have been failed to cure coronavirus disease 2019 (COVID-19) patients. However, at least two drug companies have applied for emergency use authorization with the United States Food and Drug Administration for their coronavirus vaccine candidates and several other vaccines are in various stages of development to determine safety and efficacy. Recently, some studies have shown the role of different human and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microRNAs (miRNAs) in the pathophysiology of COVID-19. miRNAs are non-coding single-stranded RNAs, which are involved in several physiological and pathological conditions, such as cell proliferation, differentiation, and metabolism. They act as negative regulators of protein synthesis through binding to the 3' untranslated region (3' UTR) of the complementary target mRNA, leading to mRNA degradation or inhibition. The databases of Google Scholar, Scopus, PubMed, and Web of Science were searched for literature regarding the importance of miRNAs in the SARS-CoV-2 life cycle, pathogenesis, and genomic mutations. Furthermore, promising miRNAs as a biomarker or antiviral agent in COVID-19 therapy are reviewed.
Topics: Animals; Antiviral Agents; Biomarkers; COVID-19; COVID-19 Vaccines; Cell Cycle; Humans; MicroRNAs; Mutation; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33382348
DOI: 10.1080/15384101.2020.1867792 -
Therapie 2022SARS-CoV-2 is a positive-sense RNA virus and it is the causative agent of the global COVID-19 outbreak. COVID-19 is similar to the previous outbreaks for instance SARS... (Review)
Review
SARS-CoV-2 is a positive-sense RNA virus and it is the causative agent of the global COVID-19 outbreak. COVID-19 is similar to the previous outbreaks for instance SARS in 2002-2003 and MERS in 2012. As the peptides have many advantages, peptide-based therapeutics might be one of the possible ways in the development of COVID-19 specific drugs. SARS-CoV-2 enters into a human via its S protein by attaching with human hACE2 present on the cell membrane in the lungs and intestines of humans. hACE2 cleaves S protein into the S1 subunit for viral attachment and the S2 subunit for fusion with the host cell membrane. The fusion mechanism forms a six-helical bundle (6-HB) structure which finally fuses the viral envelope with the host cell membrane. hACE2 based peptides such as SBP1 and Spikeplug have shown their potential as antiviral agents. S protein-hACE2 interaction and the SARS-CoV-2 fusion machinery play a crucial part in human viral infection. It is evident that if these interactions could be blocked successfully and efficiently, it could be the way to find the drug for COVID-19. Several peptide-based inhibitors are potent inhibitors of S protein-hACE2 interaction. Similarly, the antiviral activity of the antimicrobial peptide, lactoferrin makes it an important candidate for the COVID-19 drug development process. A candidate drug, RhACE2-APN01 based on recombinant hACE2 peptide has already entered phase II clinical trials. This review sheds light on different aspects of the feasibility of using peptide-based therapeutics as the promising therapeutic route for COVID-19.
Topics: Antiviral Agents; Humans; Peptides; SARS-CoV-2; Spike Glycoprotein, Coronavirus; COVID-19 Drug Treatment
PubMed: 34689960
DOI: 10.1016/j.therap.2021.09.007 -
Journal of Virology Jun 2022Effective broad-spectrum antivirals are critical to prevent and control emerging human coronavirus (hCoV) infections. Despite considerable progress made toward...
Effective broad-spectrum antivirals are critical to prevent and control emerging human coronavirus (hCoV) infections. Despite considerable progress made toward identifying and evaluating several synthetic broad-spectrum antivirals against hCoV infections, a narrow therapeutic window has limited their success. Enhancing the endogenous interferon (IFN) and IFN-stimulated gene (ISG) response is another antiviral strategy that has been known for decades. However, the side effects of pegylated type-I IFNs (IFN-Is) and the proinflammatory response detected after delayed IFN-I therapy have discouraged their clinical use. In contrast to IFN-Is, IFN-λ, a dominant IFN at the epithelial surface, has been shown to be less proinflammatory. Consequently, we evaluated the prophylactic and therapeutic efficacy of IFN-λ in hCoV-infected airway epithelial cells and mice. Human primary airway epithelial cells treated with a single dose of IFN-I (IFN-α) and IFN-λ showed similar ISG expression, whereas cells treated with two doses of IFN-λ expressed elevated levels of ISG compared to that of IFN-α-treated cells. Similarly, mice treated with two doses of IFN-λ were better protected than mice that received a single dose, and a combination of prophylactic and delayed therapeutic regimens completely protected mice from a lethal Middle East respiratory syndrome CoV (MERS-CoV) infection. A two-dose IFN-λ regimen significantly reduced lung viral titers and inflammatory cytokine levels with marked improvement in lung inflammation. Collectively, we identified an effective regimen for IFN-λ use and demonstrated the protective efficacy of IFN-λ in MERS-CoV-infected mice. Effective antiviral agents are urgently required to prevent and treat individuals infected with SARS-CoV-2 and other emerging viral infections. The COVID-19 pandemic has catapulted our efforts to identify, develop, and evaluate several antiviral agents. However, a narrow therapeutic window has limited the protective efficacy of several broad-spectrum and CoV-specific antivirals. IFN-λ is an antiviral agent of interest due to its ability to induce a robust endogenous antiviral state and low levels of inflammation. Here, we evaluated the protective efficacy and effective treatment regimen of IFN-λ in mice infected with a lethal dose of MERS-CoV. We show that while prophylactic and early therapeutic IFN-λ administration is protective, delayed treatment is detrimental. Notably, a combination of prophylactic and delayed therapeutic administration of IFN-λ protected mice from severe MERS. Our results highlight the prophylactic and therapeutic use of IFN-λ against lethal hCoV and likely other viral lung infections.
Topics: Animals; Antiviral Agents; Coronavirus Infections; Humans; Interferons; Mice; Middle East Respiratory Syndrome Coronavirus; Interferon Lambda
PubMed: 35588276
DOI: 10.1128/jvi.00364-22 -
Cells Sep 2020The small molecule macrocyclic lactone ivermectin, approved by the US Food and Drug Administration for parasitic infections, has received renewed attention in the last... (Review)
Review
The small molecule macrocyclic lactone ivermectin, approved by the US Food and Drug Administration for parasitic infections, has received renewed attention in the last eight years due to its apparent exciting potential as an antiviral. It was identified in a high-throughput chemical screen as inhibiting recognition of the nuclear localizing Human Immunodeficiency Virus-1 (HIV-1) integrase protein by the host heterodimeric importin (IMP) α/β1 complex, and has since been shown to bind directly to IMPα to induce conformational changes that prevent its normal function in mediating nuclear import of key viral and host proteins. Excitingly, cell culture experiments show robust antiviral action towards HIV-1, dengue virus (DENV), Zika virus, West Nile virus, Venezuelan equine encephalitis virus, Chikungunya virus, Pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19). Phase III human clinical trials have been completed for DENV, with >50 trials currently in progress worldwide for SARS-CoV-2. This mini-review discusses the case for ivermectin as a host-directed broad-spectrum antiviral agent for a range of viruses, including SARS-CoV-2.
Topics: Animals; Antiviral Agents; Betacoronavirus; COVID-19; Cell Line; Chlorocebus aethiops; Coronavirus Infections; Dengue; Dengue Virus; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Ivermectin; Pandemics; Pneumonia, Viral; SARS-CoV-2; Vero Cells; Zika Virus; Zika Virus Infection
PubMed: 32942671
DOI: 10.3390/cells9092100 -
Microbiology Spectrum Feb 2023The periodic emergence of infectious disease poses a serious threat to human life. Among the causative agents, including pathogenic bacteria and fungi, enveloped viruses...
The periodic emergence of infectious disease poses a serious threat to human life. Among the causative agents, including pathogenic bacteria and fungi, enveloped viruses have caused global pandemics. In the last 10 years, outbreaks of severe acute respiratory syndrome coronavirus 2 disease, severe acute respiratory syndrome, and Middle East respiratory syndrome have all been caused by enveloped viruses. Among several paths of secondary transmission, inhalation of aerosols containing saliva with sputum droplets from infected patients is the major path. To prevent these infectious diseases, mass use of antiviral agents is essential. The yeast-derived vacuole is a small organelle in which hydrolytic enzymes are concentrated. It is an intracellular organ with an excellent ability to process old organelles and bacteria and viruses that have invaded from the outside and can be present in sufficient quantity to be called a kind of enzyme bomb. We confirmed the inhibition of virus infection and structural collapse by vacuole treatment. Among several enzymes, proteases affected Phi6 infectivity. This study tried to isolate these vacuoles from yeast and use them as an antiviral agent for virus treatment, which is a recent issue. We confirmed that viral infectivity was inactivated, and structure collapsed through vacuole treatment. This paper is meaningful in that extracellularly isolated yeast-derived vacuoles are a first attempt to utilize vacuoles for viral treatment. The study assesses the vacuoles isolated from the yeast Saccharomyces cerevisiae as green antiviral agents to decrease the concerns about massive use of chemical antiviral agents and its side effects. To prevent the spreading of infectious diseases, personal or public use of antiviral agents is encouraged. The concern about the active compounds of these chemical antiviral agents has grown. Active compounds of antiviral agents have potential side effects on human health and the environment. Our proposed approach suggests effective and green antivirus material from a nonhazardous yeast strain. Also, large-scale production using a fermentation process can allow cost-effectiveness. The results showed sufficient reduced infectivity by vacuole treatment. The exposed vacuole can play the roles of both enzyme bomb to the virus and renewable nutrient source in the ecosystem.
Topics: Humans; Saccharomyces cerevisiae; Vacuoles; Ecosystem; COVID-19; Viruses; Antiviral Agents
PubMed: 36688634
DOI: 10.1128/spectrum.02661-22 -
European Journal of Medicinal Chemistry Apr 2021In current scenario, various heterocycles have come up exhibiting crucial role in various medicinal agents which are valuable for mankind. Out of diverse range of... (Review)
Review
In current scenario, various heterocycles have come up exhibiting crucial role in various medicinal agents which are valuable for mankind. Out of diverse range of heterocycle, quinoline scaffold have been proved to play an important role in broad range of biological activities. Several drug molecules bearing a quinoline molecule with useful anticancer, antibacterial activities etc have been marketed such as chloroquine, saquinavir etc. Owing to their broad spectrum biological role, various synthetic strategies such as Skraup reaction, Combes reaction etc. has been developed by the researchers all over the world. But still the synthetic methods are associated with various limitations as formation of side products, use of expensive metal catalysts. Thus, several efforts to develop an efficient and cost effective synthetic protocol are still carried out till date. Moreover, quinoline scaffold displays remarkable antiviral activity. Therefore, in this review we have made an attempt to describe recent synthetic protocols developed by various research groups along with giving a complete explanation about the role of quinoline derivatives as antiviral agent. Quinoline derivatives were found potent against various strains of viruses like zika virus, enterovirus, herpes virus, human immunodeficiency virus, ebola virus, hepatitis C virus, SARS virus and MERS virus etc.
Topics: Animals; Antiviral Agents; Cell Line, Tumor; Humans; Quinolines; Virus Diseases; Viruses
PubMed: 33609889
DOI: 10.1016/j.ejmech.2021.113220 -
Clinical Microbiology and Infection :... Aug 2020Repurposing hydroxychloroquine (HCQ) and chloroquine (CQ) as antiviral agents is a re-emerging topic with the advent of new viral epidemics. (Review)
Review
BACKGROUND
Repurposing hydroxychloroquine (HCQ) and chloroquine (CQ) as antiviral agents is a re-emerging topic with the advent of new viral epidemics.
AIMS
To summarize evidence from human clinical studies for using HCQ or CQ as antiviral agents for any viral infection.
SOURCES
PubMed, EMBASE, Scopus, Web of Science for published studies without time or language restrictions; Cochrane Clinical Trial Registry and Chinese Clinical Trials Registry for trials registered after 2015; MedRxiv for preprints within the last 12 months.
CONTENT
Study eligibility criteria were interventional and prospective observational studies (with or without a control group). Participants were adults and children with a confirmed viral infection. Interventions included the use of CQ or HCQ as antiviral agent in one or more groups of the study. Two authors independently screened abstracts, and all authors agreed on eligible studies. A meta-analysis was planned if studies were available which were similar in terms of participants, intervention, comparator and outcomes. Nineteen studies (including two preprints) were eligible (HIV 8, HCV 2, dengue 2, chikungunya 1, COVID-19 6). Nine and ten studies assessed CQ and HCQ respectively. Benefits of either drug for viral load suppression in HIV are inconsistent. CQ is ineffective in curing dengue (high-certainty evidence) and may have little or no benefit in curing chikungunya (low-certainty evidence). The evidence for COVID-19 infection is rapidly evolving but at this stage we are unsure whether either CQ or HCQ has any benefit in clearing viraemia (very-low-certainty evidence).
IMPLICATIONS
Using HCQ or CQ for HIV/HCV infections is now clinically irrelevant as other effective antivirals are available for viral load suppression (HIV) and cure (HCV). There is no benefit of CQ in dengue, and the same conclusion is likely for chikungunya. More evidence is needed to confirm whether either HCQ or CQ is beneficial in COVID-19 infection.
Topics: Adult; Antiviral Agents; Betacoronavirus; COVID-19; Child; Chloroquine; Clinical Trials as Topic; Coronavirus Infections; Drug Repositioning; Humans; Hydroxychloroquine; Observational Studies as Topic; Pandemics; Pneumonia, Viral; SARS-CoV-2; Treatment Outcome; Viral Load
PubMed: 32470568
DOI: 10.1016/j.cmi.2020.05.016 -
Cold Spring Harbor Perspectives in... Apr 2021In the last few years, several new direct-acting influenza antivirals have been licensed, and others have advanced in clinical development. The increasing diversity of... (Review)
Review
In the last few years, several new direct-acting influenza antivirals have been licensed, and others have advanced in clinical development. The increasing diversity of antiviral classes should allow an adequate public health response should a resistant virus to one agent or class widely circulate. One new antiviral, baloxavir marboxil, has been approved in the United States for treatment of influenza in those at high risk of developing influenza-related complications. Except for intravenous zanamivir in European Union countries, no antivirals have been licensed specifically for the indication of severe influenza or hospitalized influenza. This review addresses recent clinical developments involving selected polymerase inhibitors, neuraminidase inhibitors, antibody-based therapeutics, and host-directed therapies. There are many knowledge gaps for most of these agents because some data are not published and multiple pivotal studies are in progress at present. This review also considers important clinical research issues, including regulatory pathways, study designs, endpoints, and target populations encountered during the clinical development of novel therapeutics.
Topics: Antiviral Agents; Drug Development; Drug Resistance, Viral; Humans; Influenza, Human; Nucleic Acid Synthesis Inhibitors
PubMed: 32041763
DOI: 10.1101/cshperspect.a038463