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July 28, 2003
Volume 81, Number 30
CENEAR 81 30 p. 9
ISSN 0009-2347


Arginase inhibitors touted as potential drug target for sexual dysfunction


In the past few years, scientists have made strides in understanding the enzyme arginase’s role as a thwarter of penile erections. Now, a new study suggests arginase may also play a similar role in female sexuality.

TEST BUNNY Rabbits were used
as models for human sexual response.
The researchers—chemistry professor David W. Christianson and graduate student Evis Cama at the University of Pennsylvania, Abdulmaged M. Traish and Noel N. Kim at Boston University School of Medicine, and their colleagues—have detected signs of arginase activity in the genitalia of female rabbits, just as was previously shown for genitalia in human males. They also demonstrate that smooth-muscle relaxation of—and thus blood flow to—the genitalia of live rabbits, both male and female, increases with administration of a small molecule that inhibits arginase [Biochemistry, 42, 8445 (2003)].

In addition, the research team obtained the crystal structure of arginase II complexed with an arginase inhibitor, making it possible to design improved inhibitors. Arginase II is one of two human arginase isozymes and the one most important in sexual biochemistry.

The results, the researchers say, point to arginase II as a potential drug target to treat female sexual dysfunction.

Until recently, the problem hasn’t received much attention. Now, researchers are addressing the issue, but they say there’s still much to learn about how issues such as blood flow affect problems unique to females, such as pain or lack of lubrication. For example, a 2001 study, conducted by Mary Lake Polan, chairman of the Stanford University obstetrics and gynecology department, along with the company ArginMax, showed that an arginine nutraceutical improved the sex lives of women more than a placebo.

The new work could shed more light on these issues, says Trinity J. Bivalacqua, an andrology researcher at Tulane University who also studies arginase in human sexual dysfunction.

Arginase interferes with a crucial step in the complicated biochemical pathway to sexual arousal, one involving arginine, an amino acid. Normally, the enzyme nitric oxide synthase breaks arginine into citrulline and NO. NO then goes on to relax smooth muscles in the genitalia, allowing blood flow to the area. But arginase foils that by binding arginine and converting it into urea.

Two molecules—S-(2-boronoethyl)-L-cysteine (BEC) and 2(S)-amino-6-boronohexanoic acid (ABH), both designed by Christianson’s group—bind tightly to the enzyme, rendering it inactive.

After showing that these arginase inhibitors increased smooth-muscle relaxation in strips of human penile tissue, the researchers turned their attention to the female system. They note that although the wildly popular drug Viagra has acquired a reputation for inducing hardy erections in the most fragile octogenarian, it doesn’t do much for women.

They also speculate that because NO synthase is present in human clitoral tissue and the vagina, perhaps arginase II also is there. Following their success with rabbits, Christianson says, the group hopes to test the inhibitors in larger mammals, such as dogs. They also plan to test the inhibitors’ oral bioavailability.

Irwin Goldstein, director of the Institute for Sexual Medicine at Boston University, says that although an arginase-targeting treatment likely won’t help the majority of female sexual problems, which are desire- or pain-based, the new work is “another part of a huge puzzle. The field of female sexual dysfunction is just developing.”


BINDING SITE Computer graphic shows the arginase inhibitor BEC (in color) bound to the active site of arginase II (purple).


Chemical & Engineering News
Copyright © 2003 American Chemical Society

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