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Journal of Medicinal Chemistry Jun 2022SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral... (Review)
Review
SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral polymerase inhibitors remdesivir and molnupiravir and the viral main protease inhibitor nirmatrelvir/ritonavir have been approved by the U.S. FDA. However, the emergence of variants of concern/interest calls for additional antivirals with novel mechanisms of action. The SARS-CoV-2 papain-like protease (PL) mediates the cleavage of viral polyprotein and modulates the host's innate immune response upon viral infection, rendering it a promising antiviral drug target. This Perspective highlights major achievements in structure-based design and high-throughput screening of SARS-CoV-2 PL inhibitors since the beginning of the pandemic. Encouraging progress includes the design of non-covalent PL inhibitors with favorable pharmacokinetic properties and the first-in-class covalent PL inhibitors. In addition, we offer our opinion on the knowledge gaps that need to be filled to advance PL inhibitors to the clinic.
Topics: Antiviral Agents; Coronavirus Papain-Like Proteases; Humans; Pandemics; Protease Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35620927
DOI: 10.1021/acs.jmedchem.2c00303 -
Expert Review of Clinical Pharmacology 2015Eradication of chronic hepatitis C virus infection improves the outcome of both liver and extrahepatic-related diseases and interferon-based regimens represented, for... (Review)
Review
Eradication of chronic hepatitis C virus infection improves the outcome of both liver and extrahepatic-related diseases and interferon-based regimens represented, for years, the standard of care to achieve this goal. Several baseline and on-treatment predictors of response, associated with a lower chance to achieve sustained virological response after interferon-based treatment, were developed. In the past few years, the advent of direct acting antivirals has dramatically modified the landscape of antiviral therapy, leading to an evolution from interferon-based to interferon-free therapies. This review will focus on the usefulness of futility stopping rules that allow the discontinuation of therapy in patients with a reduced chance to obtain sustained virological response if treated with interferon-containing regimens.
Topics: Antiviral Agents; Hepatitis C, Chronic; Humans; Interferons; Polyethylene Glycols; Treatment Outcome
PubMed: 26437265
DOI: 10.1586/17512433.2015.1090872 -
Population Health Management Dec 2022Oral antivirals for COVID-19 can be game changers in low- and middle-income countries (LMICs). Challenges that may hinder current and future oral antiviral rollouts span...
Oral antivirals for COVID-19 can be game changers in low- and middle-income countries (LMICs). Challenges that may hinder current and future oral antiviral rollouts span use in special populations, drug-drug and herb-drug interactions, adverse events, development of resistance, black markets, and equity in access and prescribing. Future antivirals may address some of these barriers; however, health systems around the world should be equipped to receive and administer COVID-19 oral antivirals. Improvements in manufacturing capacity, community engagement, capacity for testing and linkage to care, and systems for surveillance and safety monitoring could "change the game" for LMICs, irrespective of any specific antiviral drug. Investments in health care infrastructure can promote resilience, not only for COVID-19 but also for future local and global health crises.
Topics: Humans; COVID-19; Antiviral Agents; Global Health; Developing Countries
PubMed: 36315439
DOI: 10.1089/pop.2022.0171 -
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 inĀ 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 -
Journal of Infection in Developing... Feb 2022Remarkable scientific breakthroughs have been made in the stride towards the development of potent and tolerable hepatitis C regimens within the last three decades.... (Review)
Review
Remarkable scientific breakthroughs have been made in the stride towards the development of potent and tolerable hepatitis C regimens within the last three decades. Earlier approaches involved the use of pegylated interferon alfa and ribavirin as standard-of-care treatment. Treating genotype 1a infection with this regimen which was at that time considered the gold standard for hepatitis C virus therapy was rife with challenges; safety and toxicity issues necessitated a rigorous quest for alternative regimens. Deeper understanding of the pathogenesis of hepatitis C virus ushered in the era of direct acting antiviral agents. These agents have been the subject of intensive research in the last two decades, leading to the development of drug classes such as protease inhibitors (e.g., grazoprevir), NS5A inhibitors (e.g., daclatasvir) and NS5B inhibitors (e.g., sofosbuvir). While many are still under development, several have been approved for hepatitis C therapy. A number of studies investigating the combination of direct acting antiviral agents with or without pegylated interferon and/or ribavirin for the treatment of chronic hepatitis have demonstrated sustained virologic response of > 90%. Given the array of direct acting antiviral agents currently available, the present landscape of hepatitis C therapy is now characterized by a gradual transition to all-oral interferon-free regimens. Despite these milestones, the WHO global target of eliminating hepatitis C as a public health problem by 2030 seems uncertain. In this review, we provide a concise account of the evolution and advancements in the development of anti-HCV regimens.
Topics: Antiviral Agents; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Interferon-alpha
PubMed: 35298416
DOI: 10.3855/jidc.14485 -
Carbohydrate Polymers Feb 2020Despite the number of approved antivirals has considerably increased, these existing drugs are not always efficacious or well-tolerated and drug-resistant virus strains... (Review)
Review
Despite the number of approved antivirals has considerably increased, these existing drugs are not always efficacious or well-tolerated and drug-resistant virus strains are rapidly emerging. Nowadays, many polysaccharides as independent or the main bioactive ingredients have been approved as medicines. The present report aims to provide systematically reorganized information on antiviral polysaccharides derived from edible and medicinal plants and mushrooms (PsEMPM) to people for better utilization of them. PsEMPM can inhibit the infection of viruses by interfering with a few steps in the virus life cycle and/or improving the host antiviral immune responses. Polyanionic nature and sulfates are in many cases required antiviral potency of PsEMPM, while it not only is a function of high charge density but also associated with distinct structural speciļ¬cities. Plenty of efforts have been devoted to achieving the discovery of novel antiviral polysaccharides, however, the detailed structural characteristics of PsEMPM still merit further in-depth investigation.
Topics: Agaricales; Antiviral Agents; Hepatitis A virus; Plant Roots; Plants, Medicinal; Polysaccharides; Virus Internalization
PubMed: 31826474
DOI: 10.1016/j.carbpol.2019.115548 -
Viruses Jun 2021Developing broad-spectrum antiviral drugs remains an important issue as viral infections continue to threaten public health. Host-directed therapy is a method that... (Review)
Review
Developing broad-spectrum antiviral drugs remains an important issue as viral infections continue to threaten public health. Host-directed therapy is a method that focuses on potential targets in host cells or the body, instead of viral proteins. Its antiviral effects are achieved by disturbing the life cycles of pathogens or modulating immunity. In this review, we focus on the development of broad-spectrum antiviral drugs that enhance the immune response. Some natural products present antiviral effects mediated by enhancing immunity, and their structures and mechanisms are summarized here. Natural products with immunomodulatory effects are also discussed, although their antiviral effects remain unknown. Given the power of immunity and the feasibility of host-directed therapy, we argue that both of these categories of natural products provide clues that may be beneficial for the discovery of broad-spectrum antiviral drugs.
Topics: Animals; Antiviral Agents; Biological Products; Drug Discovery; Humans; Immunomodulating Agents; Mice; Virus Diseases; Virus Replication; Viruses
PubMed: 34203182
DOI: 10.3390/v13071257 -
Pharmacology & Therapeutics Jul 2022Favipiravir, a broad-spectrum RNA-dependent RNA polymerase inhibitor, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at... (Review)
Review
Favipiravir, a broad-spectrum RNA-dependent RNA polymerase inhibitor, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at significantly lower concentrations than the plasma trough levels achieved by the dosage adopted for influenza treatment and exhibits efficacy against coronavirus disease 2019 (COVID-19) pneumonia. Although high doses of favipiravir are required due to the molecule being a purine analog, its conversion into the active form in infected cells with active viral RNA synthesis enhances the antiviral specificity and selectivity as a chain terminator with lethal mutagenesis. Another characteristic feature is the lack of generation of favipiravir-resistant virus. COVID-19 pneumonia is caused by strong cell-mediated immunity against virus-infected cells, and the inflammatory response induced by adaptive immunity continues to peak for 3 to 5 days despite antiviral treatment. This has also been observed in herpes zoster (HZ) and cytomegalovirus (CMV) pneumonia. Inflammation due to an immune response may mask the effectiveness of favipiravir against COVID-19 pneumonia. Favipiravir significantly shortened the recovery time in patients with mild COVID-19 pneumonia by 3 days with the start of treatment by the 5th day of symptom onset. Since both CMV and COVID-19 pneumonia are caused by adaptive immunity and prevention of cytomegalovirus pneumonia is the standard treatment due to difficulties in treating refractory CMV pneumonia, COVID-19 pneumonia should be prevented with early treatment as well. In the present study, we have comprehensively reviewed the optimal antiviral therapy for COVID-19 based on clinical trials of favipiravir for the treatment of COVID-19 pneumonia and the concurrently established therapies for other viral infections, particularly HZ and CMV pneumonia. Optimally, antivirals should be administered immediately after COVID-19 diagnosis, similar to that after influenza diagnosis, to prevent COVID-19 pneumonia and complications resulting from microangiopathy.
Topics: Amides; Antiviral Agents; COVID-19 Testing; Cytomegalovirus Infections; Humans; Influenza, Human; Pyrazines; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35121001
DOI: 10.1016/j.pharmthera.2022.108121 -
Molecules (Basel, Switzerland) Nov 2022Essential oils (EOs) are chemical substances, mostly produced by aromatic plants in response to stress, that have a history of medicinal use for many diseases. In the... (Review)
Review
Essential oils (EOs) are chemical substances, mostly produced by aromatic plants in response to stress, that have a history of medicinal use for many diseases. In the last few decades, EOs have continued to gain more attention because of their proven therapeutic applications against the flu and other infectious diseases. Influenza (flu) is an infectious zoonotic disease that affects the lungs and their associated organs. It is a public health problem with a huge health burden, causing a seasonal outbreak every year. Occasionally, it comes as a disease pandemic with unprecedentedly high hospitalization and mortality. Currently, influenza is managed by vaccination and antiviral drugs such as Amantadine, Rimantadine, Oseltamivir, Peramivir, Zanamivir, and Baloxavir. However, the adverse side effects of these drugs, the rapid and unlimited variabilities of influenza viruses, and the emerging resistance of new virus strains to the currently used vaccines and drugs have necessitated the need to obtain more effective anti-influenza agents. In this review, essential oils are discussed in terms of their chemistry, ethnomedicinal values against flu-related illnesses, biological potential as anti-influenza agents, and mechanisms of action. In addition, the structure-activity relationships of lead anti-influenza EO compounds are also examined. This is all to identify leading agents that can be optimized as drug candidates for the management of influenza. Eucalyptol, germacrone, caryophyllene derivatives, eugenol, terpin-4-ol, bisabolene derivatives, and camphecene are among the promising EO compounds identified, based on their reported anti-influenza activities and plausible molecular actions, while nanotechnology may be a new strategy to achieve the efficient delivery of these therapeutically active EOs to the active virus site.
Topics: Humans; Oils, Volatile; Antiviral Agents; Oseltamivir; Influenza, Human; Orthomyxoviridae
PubMed: 36431899
DOI: 10.3390/molecules27227797 -
Molecules (Basel, Switzerland) Mar 2022DNA methylation, as one of the major means of epigenesis change, makes a large difference in the spatial structure of chromatin, transposable element activity and,... (Review)
Review
DNA methylation, as one of the major means of epigenesis change, makes a large difference in the spatial structure of chromatin, transposable element activity and, fundamentally, gene transcription. It has been confirmed that DNA methylation is closely related to innate immune responses. Decitabine, the most efficient available DNA methyltransferase inhibitor, has demonstrated exhilarating immune activation and antiviral effects on multiple viruses, including HIV, HBV, HCV, HPV and EHV1. This review considers the role of decitabine in regulating innate immune responses and antiviral ability. Understanding the complex transcriptional and immune regulation of decitabine could help to identify and validate therapeutic methods to reduce pathogen infection-associated morbidity, especially virus infection-induced morbidity and mortality.
Topics: Antiviral Agents; Cognition; Decitabine; Immunity, Innate; Immunomodulation
PubMed: 35335337
DOI: 10.3390/molecules27061973