Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia

Abstract

Acyclic nucleoside phosphonates (ANPs) are well-known for their antiviral properties, three of them being approved for the treatment of human immunodeficiency virus infection (tenofovir), chronic hepatitis B (tenofovir and adefovir) or human cytomegalovirus retinitis (cidofovir). In addition, cidofovir is mostly used off-label for the treatment of infections caused by several DNA viruses other than cytomegalovirus, including papilloma- and polyomaviruses, which do not encode their own DNA polymerases. There is considerable interest in understanding why cidofovir is effective against these small DNA tumor viruses. Considering that papilloma- and polyomaviruses cause diseases associated either with productive infection (characterized by high production of infectious virus) or transformation (where only a limited number of viral proteins are expressed without synthesis of viral particles), it can be envisaged that cidofovir may act as antiviral and/or antiproliferative agent. The aim of this review is to discuss the advances in recent years in understanding the mode of action of ANPs as antiproliferative agents, given the fact that current data suggest that their use can be extended to the treatment of non-viral related malignancies.

Treatment and prevention of cytomegalovirus infection in heart and lung transplantation: an update

“…Also this acyclic nucleotide analogue impact CMV replication by inhibiting DNA polymerase but, as opposed to (val)ganciclovir, it needs to be phosphorylated by cellular kinase and not be UL 97. 47 Nevertheless, induction of cross-resistance with mutation also of UL54 has often been observed with cidofovir, limiting its use in very selected cases or as part of a combined therapy: although not supported by controlled studies, cidofovir, as well as foscarnet, may be administered in association with CMV hyperimmune globulins (CMVIG). 13,42 Three novel drugs may soon be available as alternative to (val)ganciclovir: maribavir, brincidofovir, letermovir.…”

Novel activities of safe-in-human broad-spectrum antiviral agents

“…In particular, valaciclovir inhibits replication of different herpesviruses and HBV (Laube et al, 2004;Vere Hodge and Field, 2013). Cidofovir and its lipid conjugate brincidofovir also inhibit replication of dsDNA viruses, such as herpesviruses, AdV, BKV, and HPV (Andrei et al, 2015). Ribavirin blocks viral RNA synthesis of FLUAV, HCV and RSV (Hong and Cameron, 2002).…”

Determination of the Absolute Configuration of (−)‐Hydroxynitrilaphos and Related Biosynthetic Questions

“…Thus, they are unrivalled in their range of possible targets . Consistent therewith phosphonates with a large variety of biological activities are known, ranging from antibacterial ( 1 ) to herbicidal ( 2 ) or antiviral ( 3 ) drugs (Figure ).…”