Affiliation:
1. CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing100050, China
Abstract
Synthetic nucleoside or nucleotide analogues played a key role to the development of antiviral
agents in past decades. However, low membrane permeability and insufficient cellular phosphorylation
impaired the biological activity of polar nucleoside drugs because they have to penetrate
the cell membrane and be phosphorylated to active metabolite stepwise by intracellular enzymes.
To overcome these limitations, diverse lipophilic prodrug modifications based on nucleoside
mono-, di-, and triphosphate were designed and put into practice to efficiently deliver nucleoside
into the target site, and bypass the rate-limited phosphorylation step. As the most successful
prodrug strategy, ProTide technology has led to the discovery of three FDA-approved antiviral
agents, including sofosbuvir, tenofovir alafenadmide, and remdesivir, which has been authorized
for emergency use in patients of COVID-19 in the US. In recent years, nucleoside di- and triphosphate
prodrugs have also made the significant progress. This review will focus on the summary of
design approach and metabolic activation path of different nucleotide prodrug strategies. The potential
application of nucleotide prodrugs for the treatment of COVID-19 was also described due to
the pandemic of SARS-CoV-2.
Funder
CAMS Innovation Fund for Medical Sciences
National Science and Technology Major Projects for “Major New Drugs Innovation and Development”
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,General Medicine
Cited by
9 articles.
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