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Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors.

ABSTRACT: Purpose of review: This review focuses on the chemical and pharmacological rationale behind the development of nucleoside antiviral prodrugs (NAPs).

Recent findings: Highly efficacious NAPs have been developed that extend and improve the quality of lives of individuals infected with HIV and hepatitis B virus (HBV), herpes viruses, and adenovirus infection in immunocompromised individuals. A very high rate of hepatitis C virus (HCV) cure is now possible using NAPs combined with other direct acting antiviral agents (DAAs).

Summary: Prodrug strategies can address the issues of poor oral bioavailability and delivery of active metabolites to the targeted cells. Additionally, NAPs demonstrate potential for improving deficiencies in oral absorption, metabolism, tissue distribution, cellular accumulation, phosphorylation, and overall potency, in addition to diminishing potential for in-vivo selection of resistant viruses. NAPs continue to be the backbone for the treatment of HIV and HBV, herpesviruses, and adenovirus infections because their active forms are potent, have long intracellular half-lives and are relatively safe with high barrier to resistance.

SUBMITTER: Hurwitz SJ

PROVIDER: S-EPMC7722247 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors.

Hurwitz Selwyn J SJ Schinazi Raymond F RF

Current opinion in HIV and AIDS 20131101 6

<h4>Purpose of review</h4>This review focuses on the chemical and pharmacological rationale behind the development of nucleoside antiviral prodrugs (NAPs).<h4>Recent findings</h4>Highly efficacious NAPs have been developed that extend and improve the quality of lives of individuals infected with HIV and hepatitis B virus (HBV), herpes viruses, and adenovirus infection in immunocompromised individuals. A very high rate of hepatitis C virus (HCV) cure is now possible using NAPs combined with other ...[more]

PMID: 24100876

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Project description:Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (Mpro) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. We also evalulate the effect of antiviral therapy on host gene expression using RNAseq and show that therapeutic intervention reduces host inflammatory response as compared to vehicle controls during acute SARS-CoV-2 infection. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.

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Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors.

Publications

Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors.

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