Biomaterial Database

Inhibition of human immunodeficiency virus reverse transcriptase by 2',3'-dideoxynucleoside triphosphates: template dependence, and combination with phosphonoformate. 1989

M C Starnes, and Y C Cheng

Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill 27599.

The 2',3'-dideoxynucleoside triphosphates (ddNTPs) are potent substrate analog inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and have clinical utility in the treatment of acquired immunodeficiency syndrome. Several issues regarding the interaction of these compounds with HIV reverse transcriptase were examined. The potency of unsubstituted ddNTPs and the 3'-azido analog of dTTP (AZTTP) was influenced by the choice of template. Both compounds were more potent with the complementary homopolymer templates than with gapped duplex DNA, although the Km for the competing dNTP was similar with different templates. The Ki for AZTTP was greater than for the unsubstituted ddNTPs with either a homopolymer or a gapped duplex DNA template. HIV reverse transcriptase incorporated ddCMP and AZTMP into primed phage m13 DNA at sites specified for insertion of dCMP and dTMP, respectively. ddCTP was more efficiently utilized as a substrate than was AZTTP. Primer elongation due to base misincorporation was observed in the absence of one dNTP. The combined effect of ddNTPs and the pyrophosphate analog phosphonoformate (PFA) on HIV reverse transcriptase was also examined, and inhibition by PFA in combination with ddTTP or AZTTP was mutually exclusive.

UI	MeSH Term	Description	Entries
D007700	Kinetics	The rate dynamics in chemical or physical systems.
D009943	Organophosphorus Compounds	Organic compounds that contain phosphorus as an integral part of the molecule. Included under this heading is broad array of synthetic compounds that are used as PESTICIDES and DRUGS.	Organophosphorus Compound,Organopyrophosphorus Compound,Organopyrophosphorus Compounds,Compound, Organophosphorus,Compound, Organopyrophosphorus,Compounds, Organophosphorus,Compounds, Organopyrophosphorus
D010746	Phosphonoacetic Acid	A simple organophosphorus compound that inhibits DNA polymerase, especially in viruses and is used as an antiviral agent.	Phosphonoacetate,Disodium Phosphonoacetate,Fosfonet Sodium,Phosphonacetic Acid,Phosphonoacetate, Disodium
D004261	DNA Replication	The process by which a DNA molecule is duplicated.	Autonomous Replication,Replication, Autonomous,Autonomous Replications,DNA Replications,Replication, DNA,Replications, Autonomous,Replications, DNA
D004279	DNA, Viral	Deoxyribonucleic acid that makes up the genetic material of viruses.	Viral DNA
D004338	Drug Combinations	Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture.	Drug Combination,Combination, Drug,Combinations, Drug
D006678	HIV	Human immunodeficiency virus. A non-taxonomic and historical term referring to any of two species, specifically HIV-1 and/or HIV-2. Prior to 1986, this was called human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV). From 1986-1990, it was an official species called HIV. Since 1991, HIV was no longer considered an official species name; the two species were designated HIV-1 and HIV-2.	AIDS Virus,HTLV-III,Human Immunodeficiency Viruses,Human T-Cell Lymphotropic Virus Type III,Human T-Lymphotropic Virus Type III,LAV-HTLV-III,Lymphadenopathy-Associated Virus,Acquired Immune Deficiency Syndrome Virus,Acquired Immunodeficiency Syndrome Virus,Human Immunodeficiency Virus,Human T Cell Lymphotropic Virus Type III,Human T Lymphotropic Virus Type III,Human T-Cell Leukemia Virus Type III,Immunodeficiency Virus, Human,Immunodeficiency Viruses, Human,Virus, Human Immunodeficiency,Viruses, Human Immunodeficiency,AIDS Viruses,Human T Cell Leukemia Virus Type III,Lymphadenopathy Associated Virus,Lymphadenopathy-Associated Viruses,Virus, AIDS,Virus, Lymphadenopathy-Associated,Viruses, AIDS,Viruses, Lymphadenopathy-Associated
D000163	Acquired Immunodeficiency Syndrome	An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive T-lymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993.	AIDS,Immunodeficiency Syndrome, Acquired,Immunologic Deficiency Syndrome, Acquired,Acquired Immune Deficiency Syndrome,Acquired Immuno-Deficiency Syndrome,Acquired Immuno Deficiency Syndrome,Acquired Immuno-Deficiency Syndromes,Acquired Immunodeficiency Syndromes,Immuno-Deficiency Syndrome, Acquired,Immuno-Deficiency Syndromes, Acquired,Immunodeficiency Syndromes, Acquired,Syndrome, Acquired Immuno-Deficiency,Syndrome, Acquired Immunodeficiency,Syndromes, Acquired Immuno-Deficiency,Syndromes, Acquired Immunodeficiency
D012194	RNA-Directed DNA Polymerase	An enzyme that synthesizes DNA on an RNA template. It is encoded by the pol gene of retroviruses and by certain retrovirus-like elements. EC 2.7.7.49.	DNA Polymerase, RNA-Directed,RNA-Dependent DNA Polymerase,Reverse Transcriptase,RNA Transcriptase,Revertase,DNA Polymerase, RNA Directed,DNA Polymerase, RNA-Dependent,RNA Dependent DNA Polymerase,RNA Directed DNA Polymerase
D013379	Substrate Specificity	A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.	Specificities, Substrate,Specificity, Substrate,Substrate Specificities