INHIBITORS OF VIRAL NUCLEIC ACID POLYMERASES: PYROPHOSPHATE ANALOGUES NLM AIDSLINE Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.

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INHIBITORS OF VIRAL NUCLEIC ACID POLYMERASES: PYROPHOSPHATE ANALOGUES

ACS Symp Ser; (401):1-16 1989. Unique Identifier : AIDSLINE ICDB/90666472
McKenna CE; Levy JN; Khawli LA; Harutunian V; Ye TG; Starnes MC; Bapat A; Cheng YC; Dept. of Chemistry, Univ. of Southern California, Los Angeles, CA; 90089-0744

Abstract: Virus-specific enzymes essential for viral nucleic acid replication or related functions are targets for inhibition by substrate or product nucleotide analogs 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 analogs of 'pyrophosphate' moieties in nucleotides. The synthesis of a series of alpha-halogenated and alpha-oxo PAA and methanediphosphonate derivatives is described and structure/activity relationships in their inhibition of several human (alpha, beta, gamma) and viral (HSV, EBV, HIV) DNA polymerases are presented. Inhibition of HIV RNA-directed DNA polymerase (reverse transcriptase) by PFA, alpha-oxophosphonoacetate and alpha-oxomethanediphosphonate is shown to be pH- and template-dependent. Combination of phosphonoacetate derivatives and antiviral nucleosides into 'hybrid' nucleotide analogs is briefly discussed. (44 Refs)
Keywords: *Antiviral Agents/CHEMICAL SYNTHESIS Chemistry Diphosphates/CHEMICAL SYNTHESIS/*PHARMACOLOGY DNA Polymerases/*ANTAGONISTS & INHIB Herpesvirus 4, Human/DRUG EFFECTS/ENZYMOLOGY/GENETICS Human HIV-1/DRUG EFFECTS/ENZYMOLOGY/GENETICS Nucleotides/CHEMICAL SYNTHESIS/*PHARMACOLOGY Phosphonoacetic Acid/*ANALOGS & DERIVATIVES/CHEMICAL SYNTHESIS/ PHARMACOLOGY RNA-Directed DNA Polymerase/*ANTAGONISTS & INHIB Simplexvirus/DRUG EFFECTS/ENZYMOLOGY/GENETICS Templates Viruses/DRUG EFFECTS/*ENZYMOLOGY/GENETICS MONOGRAPHKWDantiviralagents/chemicalsynthesischemistrydiphosphates/chemicalsynthesis/KWDpharmacologydnapolymerases/KWDantagonists&inhibherpesvirus4,human/drugeffects/enzymology/geneticshumanhiv-1/drugeffects/enzymology/geneticsnucleotides/chemicalsynthesis/KWDpharmacologyphosphonoaceticacid/KWDanalogs&derivatives/chemicalsynthesis/pharmacologyrna-directeddnapolymerase/KWDantagonists&inhibsimplexvirus/drugeffects/enzymology/geneticstemplatesviruses/drugeffects/KWDenzymology/geneticsmonograph
910228
M9120715

Copyright © 1991 - National Library of Medicine. Reproduced under license with the National Library of Medicine, Bethesda, MD.

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