Open AccessThe Nitric Oxide Prodrug V-PROLI/NO Inhibits Cellular Uptake of Proline
Author(s) -
Sam Y. Hong,
Gregory L. Borchert,
Anna Maciąg,
Rahul S. Nandurdikar,
Joseph E. Saavedra,
Larry K. Keefer,
James M. Phang,
Harinath Chakrapani
Publication year - 2010
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml1000905
Subject(s) - prodrug , proline , nitric oxide , chemistry , in vivo , biochemistry , biophysics , amino acid , biology , microbiology and biotechnology , organic chemistry
V-PYRRO/NO is a well studied nitric oxide (NO) prodrug which has been shown to protect human liver cells from arsenic, acetaminophen, and other toxic assaults in vivo. Its proline-based analogue, V-PROLI/NO, was designed to be a more biocompatible form that decomposes to the naturally occurring metabolites of proline, NO, and glycolaldehyde. Like V-PYRRO/NO, this cytochrome P450-activated prodrug was previously assumed to passively diffuse through the cellular membrane. Using (14)C-labeled proline in a competition assay, we show that V-PROLI/NO is transported through proline transporters into multiple cell lines. A fluorescent NO-sensitive dye (DAF-FM diacetate) and nitrite excretion indicated elevated intracellular NO release after metabolism over V-PYRRO/NO. These results also allowed us to predict and design a more permeable analogue, V-SARCO/NO. We report a proline transporter-based strategy for the selective transport of NO prodrugs that may have enhanced efficacy and aid in development of further NO prodrugs with increased permeability.