Enantiomeric selectivity of carbovir transport.
Carbovir (9-[4 alpha-(hydroxymethyl)cyclopent-2-ene-1 alpha-yl]guanine) (CBV) is a carbocyclic analogue of 2',3'-dideoxyguanosine that exhibits potent and selective in vitro activity against human immunodeficiency virus. Antiviral activity is associated with only the (-)-enantiomer. The transport characteristics of both (-)-CBV and (+)-CBV were investigated in human erythrocytes at 37 degrees C using a papaverine-stop assay. The influx of both enantiomers appeared saturable and was inhibited greater than 90% by a combination of adenine (a low Km permeant of the nucleobase carrier) and dilazep (a potent inhibitor of nucleoside transport). The influx of (-)-CBV and (+)-CBV proceeded primarily via the nucleobase carrier with Vmax (picomoles/second/5 microliters of cells)/Km (millimolar) values of 17/0.12 and 140/1.9, respectively. To a lesser extent, the influx of (-)-CBV and (+)-CBV also occurred via the nucleoside transporter. Although both compounds exhibited a similar low affinity for this latter carrier (Km approximately 2 mM), the Vmax for (-)-CBV influx was approximately 4-fold higher than the Vmax for (+)-CBV influx. We conclude that both CBV enantiomers enter human erythrocytes by two transporters that are enantiomerically selective.
Mahony
W B
WB
Division of Experimental Therapy, Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
Domin
B A
BA
Daluge
S M
SM
Miller
W H
WH
Zimmerman
T P
TP
D000998:Antiviral Agents / Q000378:metabolism; D001692:Biological Transport; D002478:Cells, Cultured; D015224:Dideoxynucleosides / Q000378:metabolism*; D004058:Diffusion; D004910:Erythrocyte Membrane / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D013237:Stereoisomerism
D000998:Antiviral Agents; D015224:Dideoxynucleosides; C057503:carbovir