Acyclic nucleoside phosphonates: a key class of antiviral drugs

Key Points Acyclic nucleoside phosphonates (ANPs) bring a new dimension to the therapy of viral infections, as they offer a broader spectrum of activity, a longer duration of antiviral action and a lower risk of resistance development compared with available treatments. The key factor underlying all these unique features is the presence of the phosphonate group, which allows ANPs to interfere with the normal pathway of nucleic acid biosynthesis, and, in particular, viral nucleic acid biosynthesis. Three ANPs (cidofovir, adefovir and tenofovir) have been marketed worldwide. They are active against virtually all key DNA viruses and retroviruses. Cidofovir has proved to be effective in the treatment of herpes-, papilloma-, polyoma-, adeno- and pox-virus infections. It has been formally approved for intravenous use in the treatment of cytomegalovirus retinitis in AIDS patients. Adefovir in its oral prodrug form, adefovir dipivoxil, has been licensed for the treatment of chronic hepatitis B virus infections. Tenofovir has been licensed in its oral prodrug form, tenofovir disoproxil fumarate (TDF), for the treatment of human immunodeficiency virus infections (that is, AIDS), and has also been marketed as a fixed-dose combination with the nucleoside analogue emtricitabine. This combination, provided as a single pill once daily, can be considered as the cornerstone of AIDS therapies. TDF alone and combined with emtriva also has great potential for the treatment of chronic hepatitis B. This article describes the history of ANPs, summarizing their chemistry, mechanisms of action and clinical applications, as well as current developments in the field. Almost 20 years after the broad antiviral activity spectrum of the first acyclic nucleoside phosphonates was described, several of these compounds have become important therapies for DNA virus and retrovirus infections. Here, we review the discovery and development of acyclic nucleoside phosphonates, focusing on cidofovir and its potential in the treatment of various herpes-, papilloma-, polyoma-, adeno- and pox-virus infections, adefovir for the treatment of hepatitis B and tenofovir for the treatment of AIDS and the prevention of HIV infections.