Meat tenderizer works because it's a protease. That is, anenzyme that breaks down the fibrous proteins that makesteak tough.

Too much protease turns meat to mush. It also breaksdown cartilage and bone in rheumatoid arthritis.

One class of such enzymes runs amok, the cysteineproteases, and have a lot to answer for in a lot of diseasesbesides arthritis _ from bone cancer and tumormetastasis to Alzheimer's disease; from cataracts to thebite of the trypanosomal parasite in Chagas disease.

Sunday and Monday, at the American Chemical Societymeeting in Chicago, a poster in the Medicinal ChemistryDivision reported on "Mechanism-Based CysteineProtease Inhibitors." Its presenter was organic chemistJames Palmer, senior scientist and project leader atKhepri Pharmaceuticals Inc., of South San Francisco.

Of the 50 attendees who expressed interest in his report,Palmer told BioWorld Today, many were most intriguedby his final graphic, which visually compared theinflammation and joint damage in a rat model of arthritiswith and without Khepri's proprietary cysteine proteaseinhibitor.

The questions they asked him concerned whether theinhibitory molecule is stable, specific and orallyavailable. Palmer observed, "of course it is."

Khepri decided to display its potential drug candidate, thefirm's founder and executive vice-president for R&D,Donald Payan, told BioWorld Today, after learning that"European patents on our first cycle of compounds willbe published this month."

And last Friday, the ACS's Journal of MedicinalChemistry carried a paper by Palmer et al., elaborating onthe topic of his poster. It defined these small-moleculeprotease inhibitors as "compounds designed to restore thenatural equilibrium of proteases [in the body]."

"There are a lot of tricks to taking a protease gene andmaking an active enzyme out of it," Payan observed.Khepri's key trick, he explained, "is to design some novelmolecules that are fundamentally inert."

This metabolic inertia allows the inhibitors to lie in waitand pounce at the instant "they encounter the activeenzyme, which turns them on, and makes them verypotent, selective and specific protease inhibitors."

When a destructive enzyme starts to cut its targetpeptide's bond, the inhibitor recognizes the imminentcatalytic chemical reaction, and moves in at high speed toinactivate it by usurping the enzyme's recognition pocket.

"That instantaneous interaction with the catalytic siteabolishes the molecules' inertness," Payan added, "sothey can shut off the catalysis."

Rats are the animal model of choice for simulating humanarthritis. Here's how Khepri experimentally demonstratedits inhibitor's potency: "First, you take a foreign protein,"Payan recounted, "in this case a mycobacterial cell wallprotein. With it, you immunize rats in paw or tail, whichgives them a brisk inflammatory and degenerativearthritis in their hind limbs.

"Over the past year," Payan continued, "in collaborationwith university scientists, we were able to show thatputting our inhibitory compound into the rats' food wasable to prevent the joint and tissue destruction, as well asthe accompanying inflammation.

"This was a very high hurdle," he pointed out. "We didn'twant to be merely anti-inflammatory Our goal was to beable to state eventually _ although obviously we're notthere yet _ that these drugs could prevent the seriousconsequences of arthritis, which is loss of joint function."

Next come studies in pharmacokinetics, to raise the bloodlevels of the compound from the present 8 to 10 percent"up toward the mid-teens." Much toxicology analysis isunder way, with more preclinical studies planned forother forms of arthritis.

"Depending upon what we find," Payan said, "weanticipate filing an IND [investigational new drugapplication] for human trials in early 1997.

"Meanwhile," he said, "being a small company goingafter a big disease that's chronic, we are actively seekingcorporate partners. We are in discussion with a number ofpharmaceutical companies, and anticipate within sixmonths having signed corporate relationships in thisfield." (See BioWorld Today, Nov. 11, 1994, p. 1.)

"We named the company `Khepri,'" the firm's vice-president of finance and administration, SandraMcNamara, explained, "after the Egyptian sun god ofrenewal and rebirth. The fact is," she divulged, "we'd runout of Greek and Roman gods, and we didn't want tohave another company with a `gene' or `immuno' in itsname." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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