title: Mechanism of anti-human immunodeficiency virus activity of beta-D-6-cyclopropylamino-2',3'-didehydro-2',3'-dideoxyguanosine.
abstract: To better understand the importance of the oxygen in the ribose ring of planar unsaturated nucleoside analogs that target human immunodeficiency virus (HIV), a 6-cyclopropyl-substituted prodrug of 2',3'-didehydro-2',3'-dideoxyguanosine (cyclo-d4G) was synthesized, and its cellular metabolism, antiviral activity, and pharmacokinetic behavior were studied. Cyclo-d4G had selective anti-HIV activity in primary blood mononuclear cells (PBMCs), effectively inhibiting the LAI strain of HIV-1 by 50% at 1.1 +/- 0.1 microM while showing 50% inhibition of cell viability at 84.5 microM. The antiviral activity in PBMCs was not markedly affected by mutations of methionine to valine at position 184 or by thymidine-associated mutations in the viral reverse transcriptase. Mutations of leucine 74 to valine and of lysine 65 to arginine had mild to moderate resistance (as high as fivefold). Studies to delineate the mechanism of cellular metabolism and activation of cyclo-d4G showed reduced potency in inhibiting viral replication in the presence of the adenosine/adenylate deaminase inhibitor 2'-deoxycoformycin, implying that the antiviral activity is due to its metabolism to the 2'-dGTP analog d4GTP. Intracellular formation of sugar catabolites illustrates the chemical and potentially enzymatic instability of the glycosidic linkage in d4G. Further studies suggest that cyclo-d4G has a novel intracellular phosphorylation pathway. Cyclo-d4G had a lower potential to cause mitochondrial toxicity than 2',3'-dideoxycytidine and 2',3'-didehydro-3'-deoxythymidine in neuronal cells. Also, cyclo-d4G had advantageous synergism with many currently used anti-HIV drugs. Poor oral bioavailability observed in rhesus monkeys may be due to the labile glycosidic bond, and special formulation may be necessary for oral delivery.
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520-8066, USA.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.forename: Brenda I
authors.initials: BI
authors.lastname: Hernandez-Santiago
authors.forename: Judy S
authors.initials: JS
authors.lastname: Mathew
authors.forename: Eisuke
authors.initials: E
authors.lastname: Murakami
authors.forename: Carey
authors.initials: C
authors.lastname: Bozeman
authors.forename: Meng-Yu
authors.initials: MY
authors.lastname: Xie
authors.forename: Ginger E
authors.initials: GE
authors.lastname: Dutschman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gullen
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Yang
authors.forename: Selwyn
authors.initials: S
authors.lastname: Hurwitz
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
authors.forename: Chung K
authors.initials: CK
authors.lastname: Chu
authors.forename: Harold
authors.initials: H
authors.lastname: McClure
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002478:Cells, Cultured; D003641:Deamination; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D008253:Macaca mulatta; D008928:Mitochondria / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects; D009173:Mycophenolic Acid / Q000494:pharmacology; D010100:Oxygen / Q000737:chemistry; D010766:Phosphorylation; D011355:Prodrugs / Q000378:metabolism
chemical_list: C501926:2-amino-6-(N-cyclopropylamino)-9-(2',3'-dideoxy-2',3'-didehydroribofuranosyl)-9H-purine; D058892:Adenosine Deaminase Inhibitors; D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D011355:Prodrugs; D000243:Adenosine Deaminase; D009173:Mycophenolic Acid; D000241:Adenosine; D010100:Oxygen