Inhibition of Herpes Simplex Virus Type 1 Helicase-Primase by (Dichloroanilino)purines and -pyrimidines
| Autor: | Joseph Gambino, Maria M. Medveczky, J. J. Crute, Peter G. Medveczky, George E. Wright, I. R. Lehman, Te-Fang Yang, Monroe J, Naseema N. Khan, C. Mulder |
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| Rok vydání: | 1995 |
| Předmět: |
DNA polymerase
DNA Primase Herpesvirus 1 Human Antiviral Agents chemistry.chemical_compound Drug Discovery Humans Gene chemistry.chemical_classification Aniline Compounds biology DNA synthesis DNA Helicases Helicase RNA Nucleotidyltransferases Molecular biology Pyrimidines Enzyme Biochemistry chemistry Purines DNA Viral biology.protein Molecular Medicine Primase Thymidine Cell Division DNA HeLa Cells |
| Zdroj: | Journal of Medicinal Chemistry. 38:1820-1825 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00010a027 |
| Popis: | Herpes simplex virus type 1 (HSV1) encodes a heterotrimeric helicase-primase comprised of the products of three of the seven DNA replication-specific genes. Several dihalo-substituted derivatives of N 2-phenylguanines and 2-anilinoadenines weakly inhibited the intrinsic DNAdependent NTPase activity of the HSVl helicase-primase, and these compounds inhibited the DNA-unwinding activity of the enzyme. The primase activity of the enzyme was strongly inhibited by 3,4- and 3,5-dichloroanilino derivatives of adenine and 2-aminopyrimidines. These compounds and nucleoside analogs of 2-(3,5-dichloroanilino)purines inhibited viral DNA synthesis in HSV1-infected HeLa cells in culture but also inhibited cellular DNA synthesis, likely as a result of inhibition of cellular primase and/or DNA polymerases. Herpes simplex virus type 1 (HSV1) encodes a heterotrimeric helicase-primase comprised of the products of the DNA replication-specific genes UL5, UL8, and UL52.I Overexpression of the products of these genes in insect cells yielded enzyme identical to that obtained from HSV1-infected CV-1 cellsa2 More recently, it has been shown that the products of the UL5 and UL52 genes form a stable subassembly of the HSVl helicaseprimase that retains all of the enzymatic activities present in the three-subunit h~loenzyme.~ The UL8 gene product has been shown to increase primase a~tivity.~ The helicase of the HSVl helicase-primase is a DNAdependent nucleoside triphosphatase (NTPase) that couples ATP or GTP hydrolysis to the unwinding of double-stranded DNA.5 The primase activity synthesizes short oligoribonucleotides that can serve as primers for subsequent DNA synthesis. Therefore, the HSVl helicase-primase contains the requisite activities that place it at the viral replication fork. Because of the central role that the helicase-primase plays in HSVl replication, we sought to identify inhibitors of each associated enzyme activity. Such compounds could serve both as probes of the catalytic sites of the enzymes and as leads in the development of antiviral drugs. 6-Anilinopyrimidines and 2-anilinopurines have been found to selectively inhibit DNA polymerases of prokaryotic and eukaryotic origin (reviewed in ref 6). Related N2-phenylguanines and their 2'deoxyribonucleosides are potent inhibitors of HSV thymidine kinases.' Inhibition by these analogs involves |
| Databáze: | OpenAIRE |
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