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Vol. 283, Issue 2, 947-954, 1997
NitroMed, Inc., Bedford, Massachusetts
Although nitrosothiols have been suggested to act as regulators of cell
(patho)physiology, little is known about the pharmacology of
nitrosylated proteins as nitric oxide (NO·) congeners. We
describe the molecular consequences of nitrosylating bovine serum
albumin (BSA) at multiple specific sites and demonstrate that the
product S-nitrosoproteins exert NO·-like
activity. The content of nucleophilic nitrosylation sites (i.e., free sulfhydryl groups) in native BSA was
increased by either reduction with dithiothreitol or thiolation with
N-acetylhomocysteine. Fourteen moles of nitrogen monoxide (NO)/mol BSA
equivalent were then selectively positioned on either the endogenous
sulfhydryl groups of reduced BSA or the homocysteine moieties of
thiolated BSA, respectively. Each resulting
S-nitrosoprotein adduct was an oligomeric mixture across
the >2000 kDa to 
66 kDa molecular mass range. The BSA-derived
S-nitrosoproteins were immunoreactive with antibodies
against native BSA but evidenced compromised long-chain fatty acid
binding. Both types of BSA-derived S-nitrosoproteins suppressed human coronary artery smooth muscle cell proliferation to a
similar degree (IC50 70 µM NO· equivalents) and
were significantly more effective antiproliferative agents than a
standard NO· donor, DETA NONOate. Antiproliferative bioactivity
reflected the NO functionalities carried by each protein, but was
independent of molecular mass of the nitrosylated BSA adducts. These
data exemplify the rational design and characterization of
protein-based S-nitrosothiols as NO· congeners
and suggest that such agents could have therapeutic potential as NO
delivery systems.
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