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Fundamental & Clinical Pharmacology Apr 2021Viral infections cause high morbidity and mortality, threaten public health, and impose a socioeconomic burden. We have seen the recent emergence of SARS-CoV-2 (Severe... (Review)
Review
Viral infections cause high morbidity and mortality, threaten public health, and impose a socioeconomic burden. We have seen the recent emergence of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), the causative agent of COVID-19 that has already infected more than 29 million people, with more than 900 000 deaths since its identification in December 2019. Considering the significant impact of viral infections, research and development of new antivirals and control strategies are essential. In this paper, we summarize 96 antivirals approved by the Food and Drug Administration between 1987 and 2019. Of these, 49 (51%) are used in treatments against human immunodeficiency virus (HIV), four against human papillomavirus, six against cytomegalovirus, eight against hepatitis B virus, five against influenza, six against herpes simplex virus, 17 against hepatitis C virus and one against respiratory syncytial virus. This review also describes future perspectives for new antiviral therapies such as nanotechnologies, monoclonal antibodies and the CRISPR-Cas system. These strategies are suggested as inhibitors of viral replication by various means, such as direct binding to the viral particle, blocking the infection, changes in intracellular mechanisms or viral genes, preventing replication and virion formation. We also observed that a large number of viral agents have no therapy available and the majority of those approved in the last 32 years are restricted to some groups, especially anti-HIV. Additionally, the emergence of new viruses and strains resistant to available antivirals has necessitated the formulation of new antivirals.
Topics: Antiviral Agents; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33011993
DOI: 10.1111/fcp.12609 -
Viruses Oct 2020Curcumin, the primary curcuminoid compound found in turmeric spice, has shown broad activity as an antimicrobial agent, limiting the replication of many different fungi,... (Review)
Review
Curcumin, the primary curcuminoid compound found in turmeric spice, has shown broad activity as an antimicrobial agent, limiting the replication of many different fungi, bacteria and viruses. In this review, we summarize recent studies supporting the development of curcumin and its derivatives as broad-spectrum antiviral agents.
Topics: Animals; Antiviral Agents; Curcuma; Curcumin; DNA Viruses; Humans; Mice; RNA Viruses; Virus Diseases
PubMed: 33142686
DOI: 10.3390/v12111242 -
Molecules (Basel, Switzerland) Feb 2022An antiviral agent is urgently needed based on the high probability of the emergence and re-emergence of future viral disease, highlighted by the recent global COVID-19... (Review)
Review
An antiviral agent is urgently needed based on the high probability of the emergence and re-emergence of future viral disease, highlighted by the recent global COVID-19 pandemic. The emergence may be seen in the discovery of the Alpha, Beta, Gamma, Delta, and recently discovered Omicron variants of SARS-CoV-2. The need for strategies besides testing and isolation, social distancing, and vaccine development is clear. One of the strategies includes searching for an antiviral agent that provides effective results without toxicity, which is well-presented by significant results for carrageenan nasal spray in providing efficacy against human coronavirus-infected patients. As the primary producer of sulfated polysaccharides, marine plants, including macro- and microalgae, offer versatility in culture, production, and post-isolation development in obtaining the needed antiviral agent. Therefore, this review will describe an attempt to highlight the search for practical and safe antiviral agents from algal-based sulfated polysaccharides and to unveil their features for future development.
Topics: Antiviral Agents; COVID-19; Humans; Microalgae; Pandemics; Polysaccharides; SARS-CoV-2
PubMed: 35208968
DOI: 10.3390/molecules27041178 -
Transplantation and Cellular Therapy Jan 2023Letermovir is an attractive cytomegalovirus (CMV) prophylactic agent, but published data in children are scarce. This retrospective chart review aimed to describe our...
Letermovir is an attractive cytomegalovirus (CMV) prophylactic agent, but published data in children are scarce. This retrospective chart review aimed to describe our experience using letermovir as CMV prophylaxis in pediatric hematopoietic cell transplantation (HCT) recipients. Pediatric patients (age <20 years) undergoing allogeneic HCT and receiving letermovir prophylaxis in the Mayo Clinic Pediatric Bone Marrow Transplant Program were eligible for inclusion in this retrospective chart review. Medical records were reviewed to evaluate letermovir dosing, CMV levels, laboratory values, and reports of adverse effects. Between October 2020 and April 2022, 9 patients age 4 to 19 years undergoing allogeneic HCT in the Pediatric Bone Marrow Transplant Program received letermovir prophylaxis, either 240 mg or 480 mg daily at a mean and median dose of 10 mg/kg/day. Letermovir was crushed and administered via nasogastric tube in 4 of 9 patients. Two patients received letermovir for secondary CMV prophylaxis after initial treatment with ganciclovir/valganciclovir, and the remaining 7 received letermovir for primary prophylaxis. One patient, a 20-kg 6-year-old female receiving 240 mg (12 mg/kg), experienced low-level CMV viremia while on letermovir. No other patients experienced CMV reactivation while on letermovir prophylaxis. In 2 patients, transient mild transaminitis was noted within the first weeks of letermovir therapy, which resolved without intervention, and its relationship to letermovir could not be clearly established. Letermovir administration was feasible and well tolerated as CMV prophylaxis in our small cohort of pediatric patients undergoing HCT. Larger, prospective studies are warranted to confirm the safety and efficacy of letermovir in children. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
Topics: Female; Humans; Child; Young Adult; Adult; Child, Preschool; Adolescent; Cytomegalovirus; Antiviral Agents; Retrospective Studies; Cytomegalovirus Infections; Valganciclovir
PubMed: 36244677
DOI: 10.1016/j.jtct.2022.10.005 -
Viruses Jun 2022Mosquito-borne flavivirus infections affect approximately 400 million people worldwide each year and are global threats to public health. The common diseases caused by... (Review)
Review
Mosquito-borne flavivirus infections affect approximately 400 million people worldwide each year and are global threats to public health. The common diseases caused by such flaviviruses include West Nile, yellow fever, dengue, Zika infection and Japanese encephalitis, which may result in severe symptoms and disorders of multiple organs or even fatal outcomes. Till now, no specific antiviral agents are commercially available for the treatment of the diseases. Numerous strategies have been adopted to develop novel and promising inhibitors against mosquito-borne flaviviruses, including drugs targeting the critical viral components or essential host factors during infection. Research advances in antiflaviviral therapy might optimize and widen the treatment options for flavivirus infection. This review summarizes the current developmental progresses and involved molecular mechanisms of antiviral agents against mosquito-borne flaviviruses.
Topics: Animals; Antiviral Agents; Culicidae; Flavivirus; Flavivirus Infections; Humans; Zika Virus; Zika Virus Infection
PubMed: 35746697
DOI: 10.3390/v14061226 -
Frontiers in Bioscience (Landmark... Sep 2022Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus disease 2019 (COVID-19), which was announced as a pandemic leading to... (Review)
Review
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus disease 2019 (COVID-19), which was announced as a pandemic leading to devastating economic and medical burden worldwide. The virus attacks the organ system across the body by binding to its receptor (for example, angiotensin converting enzyme 2) on the surface of the host cell of various organs. The patients present with a variety of pathological symptoms ranging from fever, cough and cytokine storm to acute respiratory distress syndrome (ARDS). Many combination therapies have been developed to combat the disease, via blocking one or more processes of the viral life cycle and/or relieving host complications simultaneously. In this review, the progress of those combination therapies containing at least one small molecule is updated. We believe it'll provide significant inspiration for further development of treatment strategy against SARS-CoV-2, especially its mutant variants.
Topics: Angiotensin-Converting Enzyme 2; Antiviral Agents; COVID-19; Humans; Pandemics; SARS-CoV-2
PubMed: 36224005
DOI: 10.31083/j.fbl2709257 -
Nature Communications Jul 2023Ensitrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro or Nsp5), is clinically useful against SARS-CoV-2 including its omicron variants....
Ensitrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro or Nsp5), is clinically useful against SARS-CoV-2 including its omicron variants. Since most omicron subvariants have reduced sensitivity to most monoclonal antibody therapies, SARS-CoV-2 resistance to other antivirals including main protease inhibitors such as ensitrelvir is a major public health concern. Here, repeating passages of SARS-CoV-2 in the presence of ensitrelvir revealed that the M49L and E166A substitutions in Nsp5 are responsible for reduced sensitivity to ensitrelvir. Both substitutions reduced in vitro virus growth in the absence of ensitrelvir. The combination of the M49L and E166A substitutions allowed the virus to largely evade the suppressive effect of ensitrelvir in vitro. The virus possessing Nsp5-M49L showed similar pathogenicity to wild-type virus, whereas the virus possessing Nsp5-E166A or Nsp5-M49L/E166A slightly attenuated. Ensitrelvir treatment of hamsters infected with the virus possessing Nsp5-M49L/E166A was ineffective; however, nirmatrelvir or molnupiravir treatment was effective. Therefore, it is important to closely monitor the emergence of ensitrelvir-resistant SARS-CoV-2 variants to guide antiviral treatment selection.
Topics: Animals; Cricetinae; COVID-19; SARS-CoV-2; Antiviral Agents
PubMed: 37454219
DOI: 10.1038/s41467-023-40018-1 -
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 -
Drugs Apr 2021Ansuvimab (ansuvimab-zykl; EBANGA™) is a human monoclonal antibody developed by Ridgeback Biotherapeutics, which binds to the glycoprotein on Zaire ebolavirus (Ebola... (Review)
Review
Ansuvimab (ansuvimab-zykl; EBANGA™) is a human monoclonal antibody developed by Ridgeback Biotherapeutics, which binds to the glycoprotein on Zaire ebolavirus (Ebola virus) to block its entry into host cells. Ansuvimab has been recently approved in the USA for the treatment of infection caused by Z. ebolavirus in adult and paediatric patients, including in neonates born to a mother who is RT-PCR positive for Z. ebolavirus infection, following the results of the PALM phase II/III trial. This article summarizes the milestones in the development of ansuvimab leading to this first approval for the treatment of infections caused by Ebola virus in adults and paediatric patients.
Topics: Antibodies, Monoclonal, Humanized; Antiviral Agents; Ebolavirus; Humans; Virus Internalization
PubMed: 33751449
DOI: 10.1007/s40265-021-01483-4 -
Angewandte Chemie (International Ed. in... Jul 2021Werner's Complex, as a cationic coordination complex (CCC), has hitherto unappreciated biological properties derived from its binding affinity to highly anionic...
Werner's Complex, as a cationic coordination complex (CCC), has hitherto unappreciated biological properties derived from its binding affinity to highly anionic biomolecules such as glycosaminoglycans (GAGs) and nucleic acids. Competitive inhibitor and spectroscopic assays confirm the high affinity to GAGs heparin, heparan sulfate (HS), and its pentasaccharide mimetic Fondaparinux (FPX). Functional consequences of this affinity include inhibition of FPX cleavage by bacterial heparinase and mammalian heparanase enzymes with inhibition of cellular invasion and migration. Werner's Complex is a very efficient condensing agent for DNA and tRNA. In proof-of-principle for translational implications, it is demonstrated to display antiviral activity against human cytomegalovirus (HCMV) at micromolar concentrations with promising selectivity. Exploitation of non-covalent hydrogen-bonding and electrostatic interactions has motivated the unprecedented discovery of these properties, opening new avenues of research for this iconic compound.
Topics: Antiviral Agents; Coordination Complexes; Cytomegalovirus; Fondaparinux; Glycosaminoglycans; Humans; Microbial Sensitivity Tests
PubMed: 34105220
DOI: 10.1002/anie.202105019