Metabolic Efficacy of Phosphate Prodrugs and the Remdesivir Paradigm

Abstract

Drugs that contain phosphates (and phosphonates or phosphinates) have intrinsic absorption issues and are therefore often delivered in prodrug forms to promote their uptake. Effective prodrug forms distribute their payload to the site of the intended target and release it efficiently with minimal byproduct toxicity. The ability to balance unwanted payload release during transit with desired release at the site of action is critical to prodrug efficacy. Despite decades of research on prodrug forms, choosing the ideal prodrug form remains a challenge which is often solved empirically. The recent emergency use authorization of the antiviral remdesivir for COVID-19 exemplifies a new approach for delivery of phosphate prodrugs by parenteral dosing, which minimizes payload release during transit and maximizes tissue payload distribution. This review focuses on the role of metabolic activation in efficacy during oral and parenteral dosing of phosphate, phosphonate, and phosphinate prodrugs. Through examining prior structure–activity studies on prodrug forms and the choices that led to development of remdesivir and other clinical drugs and drug candidates, a better understanding of their ability to distribute to the planned site of action, such as the liver, plasma, PBMCs, or peripheral tissues, can be gained. The structure–activity relationships described here will facilitate the rational design of future prodrugs.

COVID-19: Characteristics and Therapeutics

“…Sofosbuvir, also known as Sovaldi, is a direct-acting antiviral drug used to treat hepatitis C in combination with other antiviral drugs such as Ribavirin, Velpatasvir, and Elbasvir [87][88][89][90]. Sofosbuvir is a pro-drug that undergoes hepatic metabolism to form the active antiviral compound 2 -deoxy-2 -α-fluoro-β-C-methyluridine-5 -triphosphate [91]. This compound acts as a nucleotide analog inhibitor for the RNA-dependent RNA polymerase enzyme, which is vital for hepatitis C viral RNA synthesis and replication.…”

Umbelliferyloxymethyl phosphonate compounds-weakly binding zinc ionophores with neuroprotective properties

“…20 Phosphonate diesters RPO(OR′) 2 are commonly studied in the context of prodrugs. [21][22][23] Phosphonate ester susceptibility to phosphatase hydrolysis varies and simple alkyl esters, methyl or ethyl, are more resistant. 21,22 Synthetic schemes for the new umbelliferyl phosphonate derivatives and analogues (structures in Fig.…”

Activation of Tenofovir Alafenamide and Sofosbuvir in the Human Lung and Its Implications in the Development of Nucleoside/Nucleotide Prodrugs for Treating SARS-CoV-2 Pulmonary Infection

“…The most recent ProTide technology is to structurally modify nucleoside/nucleotide analogs to aryloxy phosphoramidite prodrugs by masking two of the oxygens of the monophosphate and monophosphonate groups with an aryloxy group and an amino acid ester group. The ProTide prodrugs have two advantages over parent nucleoside/nucleotide forms: (1) great cell permeability due to low polarity; (2) rapid intracellular activation by avoiding the rate-limiting monophosphorylating process [3,[5][6][7]. There are at least three FDA-approved ProTide prodrugs, including tenofovir alafenamide (TAF), sofosbuvir (SBV), and remdesivir (RDV) (Figure 1).…”