2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]-thiocarbonohydrazone (A1110U), a potent inactivator of ribonucleotide reductases of herpes simplex and varicella-zoster viruses and a potentiator of acyclovir.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 86 ·No. 3 ·1989-02-00 ·Pages 1051-5

Spector T, Harrington JA, Morrison RW, Lambe CU, Nelson DJ, Averett DR, Biron K, Furman PA

Abstract

2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]thiocarbonohydrazone (A1110U) was found to be a potent inactivator of the ribonucleotide reductases (EC 1.17.4.1) encoded by herpes simplex virus types 1 and 2 and by varicella-zoster virus and to be a weaker inactivator of human ribonucleotide reductase. It also markedly potentiated the antiherpetic activity of acyclovir against these viruses in tissue culture. A1110U both decreased the dGTP pool that builds up when infected cells are treated with acyclovir and induced a large increase in the pool of acyclovir triphosphate. The resultant 100-fold increase in the ratio of the concentrations of acyclovir triphosphate to dGTP should facilitate the binding of the fraudulent nucleotide to its target enzyme, herpes virus-encoded DNA polymerase, and could account for the synergy between A1110U and acyclovir. A similar change in the acyclovir triphosphate-to-dGTP ratio was previously reported to be induced by another ribonucleotide reductase inhibitor, 2-acetylpyridine 4-(2-morpholinoethyl)thiosemicarbazone (A723U). However, A1110U is considerably more potent and may have better clinical potential. Synergistic toxic interactions between A1110U and acyclovir were not detected in uninfected cells.

MeSH Terms

Acyclovir/pharmacology Antiviral Agents/pharmacology Drug Synergism Herpesvirus 3, Human/drug effects,enzymology,physiology Hydrazones/chemical synthesis,pharmacology Kinetics Pyridines/chemical synthesis,pharmacology Ribonucleotide Reductases/antagonists & inhibitors,isolation & purification Simplexvirus/drug effects,enzymology,physiology Virus Replication/drug effects

Chemicals

Antiviral Agents Hydrazones Pyridines A 1110U Ribonucleotide Reductases Acyclovir

Authors & Affiliations

8 authors, click to expand affiliations / ORCID

Spector T

Division of Experimental Therapy, Wellcome Research Laboratories, Research Triangle Park, NC 27709.

Harrington J A

Morrison R W

Lambe C U

Nelson D J

Averett D R

Biron K

Furman P A

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Article Info

Journal

Proceedings of the National Academy of Sciences of the United States of America

Abbr.

Proc Natl Acad Sci U S A

ISSN

0027-8424

DOI

10.1073/pnas.86.3.1051

Published

1989-02-00

Pages

1051-5

Language

English

Region

United States

NLM ID

7505876

PMCID

PMC286619

Subset

External Links

PubMed source DOI: 10.1073/pnas.86.3.1051 PMC Full Text View journal details

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2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]-thiocarbonohydrazone (A1110U), a potent inactivator of ribonucleotide reductases of herpes simplex and varicella-zoster viruses and a potentiator of acyclovir.

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