Alpha-Carboxynucleoside Phosphonates: Direct-Acting Inhibitors of Viral DNA Polymerases

Abstract

Acyclic nucleoside phosphonates represent a well-defined class of clinically used nucleoside analogs. All acyclic nucleoside phosphonates need intracellular phosphorylation before they can bind viral DNA polymerases. Recently, a novel class of alpha-carboxynucleoside phosphonates have been designed to mimic the natural 2′-deoxynucleotide 5′-triphosphate substrates of DNA polymerases. They contain a carboxyl group in the phosphonate moiety linked to the nucleobase through a cyclic or acyclic bridge. Alpha-carboxynucleoside phosphonates act as viral DNA polymerase inhibitors without any prior requirement of metabolic conversion. Selective inhibitory activity against retroviral reverse transcriptase and herpesvirus DNA polymerases have been demonstrated. These compounds have a unique mechanism of inhibition of viral DNA polymerases, and provide possibilities for further modifications to optimize and fine tune their antiviral DNA polymerase spectrum.

H-Phosphonate Chemistry in the Synthesis of Electrically Neutral and Charged Antiviral and Anticancer Pronucleotides

“…It is not surprising that the presence of two different phosphorus centers in one molecule stimulated the new concept of phosphonate-phosphates as nucleotide prodrugs. It could be assumed that phosphonate-phosphates bearing biologically active nucleoside moieties on the P-C and P V parts would undergo decomposition with the formation of at least two active compounds, namely, nucleoside phosphonate and nucleotide [for a review, see (Hecker and Erion, 2008;Balzarini et al, 2019]. Alkyl phosphonate-phosphates were obtained by the rearrangement of the respective gem-diphosphonates (Nicholson and Vaughn, 1971;Gancarz and Gancarz, 1993) of type 23 and found therapeutic applications (Nguyen et al, 1987;Turhanen et al, 2000).…”

Synthesis and Evaluation of Prodrugs of α-Carboxy Nucleoside Phosphonates

“…Recently, we described the design, synthesis, and evaluation of a novel class of α-carboxy nucleoside phosphonates (α-CNPs), e.g., 1 (Figure ), which are potent inhibitors of HIV-1 reverse transcriptase (RT) in cell-free assays. − In addition, this class displays activity against a range of viral polymerases including Herpes virus DNA polymerases . Significantly, these phosphonates do not require phosphorylation to exhibit activity, in sharp contrast to other phosphononucleosides, which have been designed as nucleoside monophosphate mimics and thus require further phosphorylation to the triphosphate in the host cells before they can be active .…”