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- | Journal: Structure-Activity Relationship of Oxacyclo- and Triazolo-Containing Respiratory Syncytial Virus Polymerase Inhibitors. (Pubmed Central) - Sep 20, 2024
Subsequent NMR conformational analysis suggested a correlation between the potency and conformations. Our efforts have fulfilled the aim of identifying linker modifications with maintained biological activity while enriching structural diversity and allowing modulations of other parameters.
- | sangivamycin (TNX-3500) / Tonix
Journal: Sangivamycin is preferentially incorporated into viral RNA by the SARS-CoV-2 polymerase. (Pubmed Central) - Sep 29, 2023
In contrast, host mRNA, affinity purified from the same infected and treated cells, contained little or no S. Sangivamycin triphosphate (STP) was synthesized to evaluate its incorporation into RNA by recombinant SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) under defined in vitro conditions. SARS-CoV-2 RdRp showed that S was not a chain terminator and S containing oligonucleotides templated as A. Though the antiviral mechanism remains to be determined, the data suggests that SARS-CoV-2 RdRp incorporates STP into SARS-CoV-2 RNA, which does not significantly impair viral RNA synthesis or the mutation rate.
- | Journal: Rational design and optimization of acylthioureas as novel potent influenza virus non-nucleoside polymerase inhibitors. (Pubmed Central) - Aug 22, 2023
Moreover, mechanistic studies indicated that these acylthiourea derivatives inhibited influenza virus proliferation by targeting influenza virus RNA-dependent RNA polymerase. Thus, 10m is a potential lead compound for the further exploration of treatment options for influenza.
- | Journal: Inhibition of the hERG potassium ion channel by different non-nucleoside human cytomegalovirus polymerase antiviral inhibitor series and the exploration of variations on a pyrroloquinoline core to reduce cardiotoxicity potential. (Pubmed Central) - May 8, 2023
An HCMV inhibitor with low hERG inhibition and reduced cytotoxicity is also described. The results suggest substitution can be fine tuned for the non-nucleoside polymerase inhibitors to reduce hERG inhibition and maintain HCMV antiviral potency.
- | Sovaldi (sofosbuvir) / Gilead
Journal: Safety considerations in the management of hepatitis C and HIV co-infection. (Pubmed Central) - Apr 25, 2023
Throughout this mechanism interact most HCV and HIV protease inhibitors and non-nucleoside polymerase inhibitors. Exposure to some HIV and HCV nucleos(t)ide analogues (e.g. tenofovir and sofosbuvir, respectively) is subject to induction/inhibition of drug transporters and requires special attention in patients with renal insufficiency.
- | Viekira Pak (ombitasvir/paritaprevir/ritonavir/dasabuvir) / AbbVie, Enanta Pharma
Journal: Overcoming Bioavailability Challenges of Dasabuvir and Enabling a Triple-Combination Direct-Acting Antiviral HCV Regimen through a Salt of Very Weak Acid for Oral Delivery. (Pubmed Central) - Jul 9, 2022
The oral delivery of dasabuvir through the salt approach has enabled the commercialization of the triple-combination direct-acting antiviral HCV regimen, Viekira Pak. The methodologies and solutions identified in targeted studies to overcome technical challenges encountered along the way (i.e., incorporation of polymers to inhibit crystallization and disproportionation and species mapping to enable salt manufacturing process, etc.) can be applied to other insoluble compounds.
- || Review, Journal: Opportunities and Challenges in Targeting the Proofreading Activity of SARS-CoV-2 Polymerase Complex. (Pubmed Central) - May 21, 2022
We also review the nucleoside analogs and non-nucleoside inhibitors known to interfere with the proofreading activity of NSP14. Although not yet validated, the potential use of non-nucleoside proofreading inhibitors in combination with chain-terminating nucleosides may be a promising avenue for the development of anti-CoV agents.
- || Sovaldi (sofosbuvir) / Gilead
Review, Journal: An Updated View on the Antiviral Therapy of Hepatitis C in Chronic Kidney Disease. (Pubmed Central) - Nov 29, 2021
However, recent data highlight that many patients with advanced CKD remain untreated, and numerous barriers to antiviral treatment of HCV still exist. Whether successful antiviral therapy with DAAs will translate into improved survival in the advanced CKD population is another point of future research.
- || methotrexate / Generic mfg.
Review, Journal: Recent developments in the medicinal chemistry of single boron atom-containing compounds. (Pubmed Central) - Nov 5, 2021
In this perspective, we aim to comprehensively review the current status of boron compounds in drug discovery, focusing especially on progress from 2015 to December 2020. We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments.
- | lamivudine HBV / Generic mfg.
Preclinical, Journal: Non-nucleoside hepatitis B virus polymerase inhibitors identified by an in vitro polymerase elongation assay. (Pubmed Central) - Sep 19, 2021
We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments. We report the development of a screening system that is useful for identifying non-nucleos(t)ide RT inhibitors.
- | remdesivir / Generic mfg.
Journal: Baicalein and Baicalin Inhibit SARS-CoV-2 RNA-Dependent-RNA Polymerase. (Pubmed Central) - May 1, 2021
As there are no antiviral agents for the prevention and treatment of this severe pathogen except for remdesivir, development of antiviral therapies to treat infected individuals remains highly urgent...Our data through cell-based and biochemical studies showed that both compounds act as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors directly and inhibit the activity of the SARS-CoV-2 RdRp, but baicalein was more potent. We also showed specific binding of baicalein to the SARS-CoV-2 RdRp, making it a potential candidate for further studies towards therapeutic development for COVID-19 as a selective non-nucleoside polymerase inhibitor.
- | Journal: Synthesis of 4'-Substituted-2'-Deoxy-2'-α-Fluoro Nucleoside Analogs as Potential Antiviral Agents. (Pubmed Central) - Dec 23, 2020
Newly prepared compounds were evaluated against RSV, but also against a panel of RNA viruses, including Dengue, West Nile, Chikungunya, and Zika viruses. Unfortunately, none of the compounds showed marked antiviral activity against these viruses.
- || Clinical, PK/PD data, Journal: Design of N-Benzoxaborole Benzofuran GSK8175 - Optimization of Human PK Inspired by Metabolites of a Failed Clinical HCV Inhibitor. (Pubmed Central) - Sep 17, 2020
An X-ray structure of NS5B protein co-crystallized with 49 revealed unique protein-inhibitor interactions mediated by an extensive network of ordered water molecules, and the first evidence of boronate complex formation within the binding pocket. In clinical studies, 49 displayed a 60-63 h half-life and a robust decrease in viral RNA levels in HCV infected patients, thereby validating our hypothesis that reducing benzylic oxidation would improve human PK and lower efficacious doses relative to 1.
- | Journal: Highly Diastereoselective Synthesis of A HCV NS5B Nucleoside Polymerase Inhibitor. (Pubmed Central) - Jul 8, 2020
This novel route features several remarkably diastereoselective and high yielding transformations, including construction of the all carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. Subsequent glycosylation reaction with activated uracil via C-1 phosphate, and installation of the cyclic phosphate group using an achiral phosphorous (III) reagent followed by oxidation provides 1.
- || pimodivir (JNJ-3872) / J&J
Clinical, P1 data, PK/PD data, Journal: Single- and Multiple-dose Pharmacokinetics and Safety of Pimodivir, a Novel, Non-Nucleoside Polymerase Basic Protein 2 Subunit Inhibitor of the Influenza A Virus Polymerase Complex, and Interaction With Oseltamivir: A Phase 1 Open-Label Study in Healthy Volunteers. (Pubmed Central) - Nov 19, 2019
Combination treatment with pimodivir and oseltamivir in healthy volunteers showed no clinically relevant drug-drug interactions. No safety concerns were identified with pimodivir 600-mg twice-daily alone or in combination with oseltamivir 75-mg twice-daily.
- | pimodivir (JNJ-3872) / J&J
Clinical, P2a data, Journal: JNJ-63623872 treatment in adult volunteers experimentally inoculated with live influenza virus: a Phase IIa, randomized, double-blind, placebo-controlled study. (Pubmed Central) - Sep 28, 2019
JNJ-63623872 has potential to not only reduce viral load but to have a clinical impact on patients as a novel treatment for influenza A virus infection. Further trials are therefore warranted to assess JNJ-63623872.
- | setrobuvir (AN598) / Roche
PK/PD data, Journal: A pharmacokinetic/viral kinetic model to evaluate treatment of chronic HCV infection with a non-nucleoside polymerase inhibitor. (Pubmed Central) - Sep 28, 2019
Further, our work suggests that patients infected with subtype 1a would need higher doses than those infected with subtype 1b to achieve the same effectiveness. Whether this is true for other non-nucleoside polymerase inhibitors needs to be examined.
- | Clinical, Review, Journal: New Direct-Acting Antivirals for the Treatment of Patients With Hepatitis C Virus Infection: A Systematic Review of Randomized Controlled Trials. (Pubmed Central) - Sep 15, 2019
This systematic review confirms that new DAAs are more effective in inducing SVR than placebo. Outside clinical trials, in real word, HCV cure with DAA regimens occurs in less than 90% of patients, so further comparative evaluations are needed to establish their long-term effects.
- | vedroprevir (GS 9451) / Gilead, Cimivir-L (sofosbuvir+ledipasvir) / Gilead, GS-9669 / Gilead
Journal, Combination therapy: The paradox of highly effective sofosbuvir-based combination therapy despite slow viral decline: can we still rely on viral kinetics? (Pubmed Central) - Jun 15, 2019
In conclusion, the rapid cure rate achieved with these combinations is largely disconnected from viral loads measured during treatment. A model assuming that rapid cure is due to a drug effect of generating non-infectious virus could be a basis for future response guided therapy.