Anti-HIV Activity of MDL 74968, a Novel Acyclonucleotide Derivative of Guanine: Drug Resistance and Drug Combination Effects in Vitro
| Autor: | Debra L. Taylor, Patrick Casara, T. M. Brennan, S.P. Ahmed, Jean-François Nave, A. S. Tyms |
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| Rok vydání: | 1996 |
| Předmět: |
0301 basic medicine
Nevirapine 030106 microbiology Lamivudine General Medicine Biology 01 natural sciences Virology Reverse transcriptase Virus 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences Zidovudine Zalcitabine medicine Adefovir Didanosine medicine.drug |
| Zdroj: | Antiviral Chemistry and Chemotherapy. 7:253-260 |
| ISSN: | 2040-2066 |
| DOI: | 10.1177/095632029600700505 |
| Popis: | MDL 74968 (9-[2-methylidene-3-(phosphonomethoxy)-propyl]guanine), a novel acyclonucleotide derivative of guanine, inhibited human immunodeficiency virus type 1 (HIV-1) replication in vitro with activity comparable to that of adefovir (PMEA; 9-(2-phosphonomethoxyethyl)adenine). MDL 74968 was investigated in combination with two licensed nucleoside analogues, zidovudine and didanosine, using a cell viability assay, and drug interactions were evaluated by the isobologram technique, by calculating combination indices and by the MacSynergy™ program. Inhibition of HIV-1 replication was only additive in both cases. MDL 74968 had equivalent antiviral activity against strains of HIV-1 HXB2 engineered to have mutations which conferred resistance to the nucleoside analogues lamivudine, didanosine and zidovudine and the non-nucleoside inhibitor of reverse transcriptase (RT) nevirapine, as against the wild type strain. Continued passage of HIV-1 RF in C8166 cells in the presence of MDL 74968 for 5 months (30 passages) failed to select drug resistant mutants. Continued passage of virus in the presence of the same concentration of adefovir for the same length of time selected a virus in a single culture, which was 3-fold resistant to adefovir and cross-resistant to MDL 74968. Genotypic characterization of this virus revealed a lysine to arginine exchange (AAA to AGA) at position 65 in the RT gene. This virus was not cross-resistant to either zidovudine or nevirapine but showed reduced sensitivity to zalcitabine, didanosine and lamivudine. Continued passage of HIV-1 RF in the presence of nevirapine or zidovudine, using similar experimental protocols selected drug resistant viruses after eight and 17 passages, respectively, but these viruses remained sensitive to adefovir and MDL 74968. |
| Databáze: | OpenAIRE |
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