Mechanism of Anti-Human Immunodeficiency Virus Activity of β-d-6-Cyclopropylamino-2′,3′-Didehydro-2′,3′-Dideoxyguanosine

摘要: To better understand the importance of oxygen in ribose ring planar unsaturated nucleoside analogs that target human immunodeficiency virus (HIV), a 6-cyclopropyl-substituted prodrug 2′,3′-didehydro-2′,3′-dideoxyguanosine (cyclo-d4G) was synthesized, and its cellular metabolism, antiviral activity, pharmacokinetic behavior were studied. Cyclo-d4G had selective anti-HIV activity primary blood mononuclear cells (PBMCs), effectively inhibiting LAI strain HIV-1 by 50% at 1.1 ± 0.1 μM while showing inhibition cell viability 84.5 μM. The PBMCs not markedly affected mutations methionine to valine position 184 or thymidine-associated viral reverse transcriptase. Mutations leucine 74 lysine 65 arginine mild moderate resistance (as high as fivefold). Studies delineate mechanism metabolism activation cyclo-d4G showed reduced potency replication presence adenosine/adenylate deaminase inhibitor 2′-deoxycoformycin, implying is due 2′-dGTP analog d4GTP. Intracellular formation sugar catabolites illustrates chemical potentially enzymatic instability glycosidic linkage d4G. Further studies suggest has novel intracellular phosphorylation pathway. lower potential cause mitochondrial toxicity than 2′,3′-dideoxycytidine 2′,3′-didehydro-3′-deoxythymidine neuronal cells. Also, advantageous synergism with many currently used drugs. Poor oral bioavailability observed rhesus monkeys may be labile bond, special formulation necessary for delivery.