Journey of remdesivir from the inhibition of hepatitis C virus to the treatment of COVID-19

Cihlář, Tomáš; Mackman, Richard L.

doi:10.1177/13596535221082773

Cited by 21 publications

(17 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, remdesivir shows strong liver-targeting properties. Remdesivir, the McGuigan (ProTide) prodrug, was initially designed for treating hepatitis C virus infection by overcoming the rate-limiting initial phosphorylation step and sustaining a high concentration of biologically active nucleotide triphosphates (NTP) in the liver ( 95 ). However, remdesivir (preferential hepatic extraction) may not be suitable for treating COVID-19 because the lungs are the primary site (type II alveolar cells) of SARS-CoV-2 infection and the most affected organs ( 96 , 97 ).…”

Section: Remdesivir: the Intravenously Administered Version Of Gs-441524mentioning

confidence: 99%

Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

Wang

Yang

Song³

2022

Front. Immunol.

View full text Add to dashboard Cite

GS-441524, an RNA‐dependent RNA polymerase (RdRp) inhibitor, is a 1′-CN-substituted adenine C-nucleoside analog with broad-spectrum antiviral activity. However, the low oral bioavailability of GS‐441524 poses a challenge to its anti-SARS-CoV-2 efficacy. Remdesivir, the intravenously administered version (version 1.0) of GS-441524, is the first FDA-approved agent for SARS-CoV-2 treatment. However, clinical trials have presented conflicting evidence on the value of remdesivir in COVID-19. Therefore, oral GS-441524 derivatives (VV116, ATV006, and GS-621763; version 2.0, targeting highly conserved viral RdRp) could be considered as game-changers in treating COVID-19 because oral administration has the potential to maximize clinical benefits, including decreased duration of COVID-19 and reduced post-acute sequelae of SARS-CoV-2 infection, as well as limited side effects such as hepatic accumulation. This review summarizes the current research related to the oral derivatives of GS-441524, and provides important insights into the potential factors underlying the controversial observations regarding the clinical efficacy of remdesivir; overall, it offers an effective launching pad for developing an oral version of GS-441524.

show abstract

Section: Remdesivir: the Intravenously Administered Version Of Gs-441524mentioning

confidence: 99%

Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

Wang

Yang

Song³

2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Antiviral drugs that can specifically target lung tissue would be ideal therapies for use. Remdesivir, the first FDA-approved antiviral for treatment of COVID-19, is a phosphoramidate adenosine analogue (Cihlar and Mackman, 2022). Recently, some of the enzymes involved in activating remdesivir in lung cells were determined to be carboxylesterase 1, cathepsin A, and histidine triad nucleotide binding protein 1 (Li et al, 2021).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Cell and Tissue Specific Metabolism of Nucleoside and Nucleotide Drugs: Case Studies and Implications for Precision Medicine

2022

Drug Metab Dispos

View full text Add to dashboard Cite

Many clinically used antiviral drugs are nucleoside or nucleotide analogue drugs, which have a unique mechanism of action that requires intracellular phosphorylation. This dependence on intracellular activation presents novel challenges for the discovery and development of nucleoside/nucleotide analogue drugs. Contrary to many small molecule drug development programs that rely on plasma pharmacokinetics and systemic exposures, the precise mechanisms that result in efficacious intracellular nucleoside triphosphate concentrations must be understood in the process of nucleoside/nucleotide drug development. The importance is highlighted here, using the following as case studies: the herpes treatment acyclovir, the cytomegalovirus therapy ganciclovir, and human immunodeficiency virus (HIV) treatments based on tenofovir, which are also in use for HIV prophylaxis. For each drug, the specificity of metabolism that results in its activation in different cells or tissues is discussed, and the implications explored. Acyclovir's dependence on a viral enzyme for activation provides selective pressure for resistance mutations.Ganciclovir is also dependent on a viral enzyme for activation, and suicide gene therapy capitalizes on that for a novel oncology treatment. The tissue of most relevance for tenofovir activation depends on its use as treatment or as prophylaxis, and the pharmacogenomics and drug-drug interactions in those tissues must be considered. Finally, differential metabolism of different tenofovir prodrugs and its effects on toxicity risk are explored. Taken together, these examples highlight the importance of understanding tissue specific metabolism for optimal use of nucleoside/nucleotide drugs in the clinic.

show abstract

“…So it is a global demand to approve those classes of therapeutics for use in COVID-19 treatment. On 22 nd October 2020, US FDA approved the first antiviral drug Remdesivir for the treatment of COVID-19, and it was initially developed to treat Hepatitis-C [31] . However, due to the exigencies of the COVID-19 pandemic, the drug authorities authorized emergency use for treating patients in critical stages.…”

Section: Classification Of Covid-19 Therapeuticsmentioning

confidence: 99%

“…Considering the extensive use of chemo drugs during API (Active Pharmaceutical Ingredient) manufacturing process, potential impurities, also called related substances, arise from the materials used like raw materials, isomers, intermediates, reagents, solvents, catalysts, etc. Few chemo drugs are genotoxic and mutagenic, which may alter the DNA sequence and lead to mutations resulting in many life-threatening disorders, including cancer and ulcers [31] .…”

Section: Classification Of Covid-19 Therapeuticsmentioning

confidence: 99%

Anti-SARS-CoV-2 Biotherapeutics and Chemotherapeutics: An Insight into Product Specifications and Marketing Dynamics

Kotra¹,

Mallem²,

Kanuri³

et al. 2022

Prog Micobes Mol Biol

View full text Add to dashboard Cite

Chemotherapeutics and biotherapeutics agents have been explored as a potential treatment for COVID-19. This study was aimed to elucidate latest update related to biotherapeutics and chemotherapeutics against COVID-19 and its variants as well as the product specifications and marketing dynamics of its pharmacotherapies. There are several chemotherapeutics that have been studied for the treatment of COVID-19, including Paxlovid (Nirmatrelvir & Ritonavir) fixed dose combination, nirmatrelvir and ritonavir fixed dose combination, Remdesivir (Vekulary/Covifor) fixed dose combination, chloroquine and hydroxychloroquine, molnupiravir, favipiravir, Infliximab (Remsima®) fixed dose combination tocilizumab (Actimera), casirivimab+imdevimab (Ronapreve) fixed dose combination, ivermectin, methylprednisole. These drugs have been repurposed for use in COVID-19 due to their antiviral properties and ability to reduce inflammation. The COVID-19 death cases have significantly reduced because of tested efficacy of advanced biotherapeutics and chemotherapeutics. As for marketing dynamics, the demand for chemotherapeutics for the treatment of COVID-19 has increased significantly since the outbreak of the pandemic. Hence, the prices of anti-viral and monoclonal antibodies in top COVID-19 affected countries is also presented here. Considering the molecular interactions, therapeutic activity, efficacy, and adverse effects, the USFDA and the WHO recommended the aforementioned drugs. The chances of approval seems favouring biotherapeutics as these have the best characteristics among the chemotherapeutics. Overall, this review contributes to the scientific understanding of the COVID-19. This can help to inform future research and development efforts and contribute to the overall advancement of knowledge in the field of medicine.

show abstract

Journey of remdesivir from the inhibition of hepatitis C virus to the treatment of COVID-19

Cited by 21 publications

References 75 publications

Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

Cell and Tissue Specific Metabolism of Nucleoside and Nucleotide Drugs: Case Studies and Implications for Precision Medicine

Anti-SARS-CoV-2 Biotherapeutics and Chemotherapeutics: An Insight into Product Specifications and Marketing Dynamics

Contact Info

Product

Resources

About