Inhibitors of Viral Nucleic Acid Polymerases

Abstract

Virus-specific enzymes essential for viral nucleic acid replication or related functions are targets for inhibition by substrate or product nucleotide analogues in which one or more P-O bonds are replaced by a P-C bond. The simplest examples of these are PFA (phosphonoformic acid ) and PAA (phosphonoacetic acid), representing analogues of 'pyrophosphate' moieties in nucleotides. The synthesis of a series of α-halogenated and α-οxο PAA and MDP (methanediphosphonate) derivatives is described and structure/activity relationships in their inhibition of several human (α,β,γ) and viral (HSV, EBV, HIV) DNA polymerases are present ed. Inhibition of HIV RNA-directed DNA polymerase (reverse transcriptase) by PFA, α-oxophosphonoacetate and α-oxomethanediphosphonate is shown to be pH-and template-dependent. Combination of phosphonoacetate derivatives and anti-viral nucleo sides into 'hybrid' nucleotide analogues is brief ly discussed.Viruses, infecting and reproducing within host cells, have long been an elusive target for chemotherapy. However, recent advances in 3

A library of nucleotide analogues terminate RNA synthesis catalyzed by polymerases of coronaviruses that cause SARS and COVID-19

“…These RdRps have low fidelity (Selisko et al, 2018), allowing them to recognize a variety of modified nucleotide analogues as substrates. Such nucleotide analogues may inhibit further RNApolymerase catalyzed RNA replication making them important candidate anti-viral agents (McKenna et al, 1989;Öberg, 2006;Eltahla et al, 2015;De Clercq and Li, 2016). RdRps in SARS-CoV and SARS-CoV-2 have nearly identical sequences (Ju et al, 2020;Elfiky, 2020).…”

Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates

“…22,23 Carbonylbisphosphonate (COBP) 17, first isolated by Quimby 24 and further investigated by McKenna, is efficient at inhibiting HIV-1 RT. 23,25,26 Compound 18 is non-inhibitory towards HIV-1 RT, however, and despite extensive efforts having been devoted to the synthesis of small molecule substituted derivatives of 15 and 18 , these efforts have usually resulted in less effective HIV-1 RT inhibitors than foscarnet. 26 The preparation and characterization of AZT 5′-COBP 19 has been described, but no biological data has been reported.…”

“…23,25,26 Compound 18 is non-inhibitory towards HIV-1 RT, however, and despite extensive efforts having been devoted to the synthesis of small molecule substituted derivatives of 15 and 18 , these efforts have usually resulted in less effective HIV-1 RT inhibitors than foscarnet. 26 The preparation and characterization of AZT 5′-COBP 19 has been described, but no biological data has been reported. 27 More recently, purine-like bisphosphonates 20 and 21 have been shown to inhibit HIV-1 RT-catalyzed synthesis.…”

A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses Causing SARS and COVID-19

“…These RdRps have low fidelity (Selisko et al 2018), allowing them to recognize a variety of modified nucleotide analogues as substrates. Such nucleotide analogues may inhibit further RNA-polymerase catalyzed RNA replication making them important candidate anti-viral agents (McKenna et al 1989;Öberg 2006;Eltahla et al 2015;De Clercq and Li 2016). RdRps in SARS-CoV and SARS-CoV-2 have nearly identical sequences (Elfiky 2020); recently, the SARS-CoV-2 RdRp was cloned (Chien et al 2020) and the RNA polymerase complex structure was determined (Gao et al 2020), which will help guide the design and study of RdRp inhibitors.…”