acyclovir and 2-6-diaminopurine

A series of acyclic selenopurine nucleosides

Topics: 2-Aminopurine; Acyclovir; Antiviral Agents; Cytomegalovirus; Guanine; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Nucleosides; Organoselenium Compounds; Prodrugs; Purines; Simplexvirus; Structure-Activity Relationship

Varicella-zoster virus (VZV) mutants were isolated under the pressure of different classes of antiviral compounds: (i) drugs that depend on the viral thymidine kinase (TK) for their activation, i.e. acyclovir (ACV), brivudin (BVDU), penciclovir (PCV) and sorivudine (BVaraU); (ii) drugs that are independent of the viral TK for their activation, i.e. 2-phosphonylmethoxyethyl (PME) derivatives of adenine (PMEA, adefovir) and 2,6-diaminopurine (PMEDAP); and (iii) drugs that do not require any metabolism to inhibit the viral DNA polymerase, i.e. foscarnet (PFA). Drug-resistant virus strains were obtained by serial passage of the OKA strain in human embryonic lung (HEL) fibroblasts and the different drug-resistant mutants were subsequently evaluated for their in vitro susceptibility to a broad range of antiviral drugs. Virus strains emerging under the pressure of ACV, BVDU and BVaraU were cross-resistant to all drugs that depend on the viral TK for activation, but remained susceptible to the acyclic nucleoside phosphonates (i.e. PMEA, PMEDAP and the 3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir)) and PFA. In contrast, the virus strains selected under pressure of PCV were resistant to PCV, ACV, PMEA and PFA; but not BVDU, BVaraU, GCV, HPMPC or HPMPA. Similar patterns of drug susceptibility were noted for the virus strains selected under the pressure of PMEA or PFA, pointing to an alteration in the viral DNA polymerase as basis for the resistant phenotype selected by PCV, as well as PMEA and PFA. In contrast, the resistant phenotype selected by ACV as well as BVDU and BVaraU may be attributed primarily to mutations in the viral TK gene. Our data thus indicate that ACV and PCV select in vitro for different drug-resistant VZV phenotypes; whether this is also the situation in vivo remains to be investigated.

Topics: 2-Aminopurine; Acyclovir; Adenine; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Cidofovir; Cytosine; DNA-Directed DNA Polymerase; Drug Resistance, Multiple, Viral; Drug Resistance, Viral; Foscarnet; Guanine; Herpesvirus 3, Human; Humans; Microbial Sensitivity Tests; Mutation; Organophosphonates; Phenotype; Selection, Genetic; Thymidine Kinase; Viral Proteins

Beginning with 3-cyclopenten-1-ylamine hydrochloride, the 5'-nor derivatives of carbocyclic 2'-deoxyguanosine (2), 2'-deoxyadenosine (3), and 2,6-diaminopurine 2'-deoxyribofuranoside (4) have been prepared. These compounds were evaluated for antiviral potential versus herpes simplex virus, varicella-zoster virus, cytomegalovirus, vaccinia virus, vesicular stomatitis virus, and human immunodeficiency virus and found to lack activity. Also, compounds 2-4 were virtually nontoxic toward the host (human diploid fibroblast ESM and HEL) cells. These biological properties may be due to the inability of 2-4 to be phosphorylated to the requisite nucleotide level that is likely to be necessary for biological activity by correlation to carbocyclic 2'-deoxyguanosine (1), which possesses significant antiviral properties as a result of conversion to its 5'-triphosphate derivative.

Topics: 2-Aminopurine; Antiviral Agents; Cytomegalovirus; Deoxyadenosines; Deoxyguanosine; Herpesvirus 3, Human; HIV-1; HIV-2; Molecular Structure; Simplexvirus; Structure-Activity Relationship; Vaccinia virus; Vesicular stomatitis Indiana virus