Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active
peptides.
L-Arginine is a guanidino group-containing
basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many
enzymes display a preference for the
arginine residue that is found in many natural substrates and in synthetic inhibitors of many
trypsin-like
serine proteases, e.g.
thrombin,
factor Xa,
factor VIIa,
trypsin, and in
integrin receptor antagonists, used to treat many
blood-coagulation disorders.
Nitric oxide (NO), which is produced by oxidation of
L-arginine in an
NADPH- and O(2)-dependent process catalyzed by
isoforms of
nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate
L-arginine, is desirable for potential
therapeutic use and for a better understanding of their conformation when bound in the
arginine binding site. The guanidino residue of
arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an
aspartic acid moiety, which provides specificity for the
basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in
enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of
arginine mimetics that can confer selective inhibition for specific
trypsin-like
serine proteases and NOS inhibitors as well as
integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of
arginine mimetics designed to mimic the function of the
arginine moiety in numerous
peptidomimetic compounds (
thrombin inhibitors,
factor Xa inhibitors,
factor VIIa inhibitors,
integrin receptor antagonists,
nitric oxide synthase inhibitors), with the aim of obtaining better activity, selectivity and oral bioavailability.