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Chemical disguises improve peptide drug.

Chemical disguises improve peptide drug

Some promising medications, if taken by mouth, get stopped by digestive juices or liver enzymes before they ever have a chance to do their work. Pharmacologists have now disguised one such drug, called a renin inhibitor, so that it can sneak into the bloodstream and pass through the liver intact.

Renin inhibitors block the production of a substance called angiotensin II, which can raise blood pressure. Clinical studies have shown that injections of renin inhibitors can lower high blood pressure, and recent findings suggest that high levels of renin may increase heart attack risk in people with moderate hypertension (SN: 4/20/91, p.245).

But daily injections are impractical as a routine treatment regimen, so researchers at Abbott Laboratories in North Chicago set out to develop an effective oral alternative. They now report successfully camouflaging renin inhibitors in two ways and testing several compounds using each strategy.

Standard renin inhibitors consist of peptides -- amino acid chains linked by amide bonds, which are particularly vulnerable to disruption by enzymes. In one approach, the Abbott team made a "nonpeptide" that acts as a renin inhibitor but escapes recognition by peptide-degrading enzymes. "There are no naturally occurring amino acids as part of the structure," Abbott pharmacologist Hollis Kleinert says.b "It's something that I think will be very useful for all sorts of medications."

In a second approach, the researchers made "dipeptides" -- two amino acids linked by an amide bond -- but they modified the bond so that enzymes wouldn't recognize it.

They then gave oral doses of these compounds to rats and tracked the drugs' survival in the body. About 20 percent of the renin inhibitor remained in active form after passing through the liver, they found. This "oral bioavailability" is double the amount considered necessary for the drug to work, Kleinert says, and four times greater than that achieved with oral administration of the standard form of the peptide.
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Title Annotation:renin inhibitors, used for lowering blood pressure
Author:Pennisi, Elizabeth
Publication:Science News
Date:Apr 27, 1991
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