Acyclic Nucleoside Phosphonates: The Art of the Prodrug

Abstract Acyclic nucleoside phosphonates (ANPs) represent a new dimension for the treatment of DNA viruses and retrovirus infections. Besides the prominent antiviral activity, ANPs have also demonstrated other interesting biological activities, such as antineoplastic and antiparasitic. Due to the presence of characteristic phosphonate functionality, ANPs rely heavily on prodrug approaches for their oral bioavailability and targeted delivery. This article will first longitudinally review the representative parent ANPs and ANP prodrugs in each of the four structural categories (i.e., HPMP, PME, PMP, and other series), focusing on the prodrug design rationales employed, resulting effects on pharmacokinetics and biological activities, as well as clinical relevance as appropriate. Then, the prodrug approaches employed for the design of ANP prodrugs will be horizontally reviewed in a dedicated section. Finally, current advances and future directions of the drug discovery of ANPs and their prodrugs will be discussed in perspective.