From alfalfa to zinc, health-food stores peddle their products as"natural" alternatives to the "harsh synthetic chemicals" thatphysicians prescribe.

Their "Mother-Nature-knows best" pitch may be relatively harmless,but it doesn't go anywhere near deep enough into what nature isreally up to. That nittiest-grittiest level is the realm of cellular andmolecular biologists, such as Vincent Manganiello at the NationalHeart, Lung and Blood Institute (NHLBI) in Bethesda, Md.

Manganiello eavesdrops on the ceaseless signaling that goes onbetween biochemical messengers outside a cell and those inside,which turn those messages into cellular responses or biologicaleffects.

Take for example the panoply of hormones, growth factors andneurotransmitters that bombard target cells with their specificendocrine agendas. Some of these pitches are sure-fire homers;others, foul balls. The batters and catchers inside the cell are cyclicnucleotides, notably the "second messengers" cAMP and cGMP.These small molecules translate the incoming impulse into a specificbiological response.

Among the enzymes that do this work, Manganiello told BioWorldToday, "are phosphodiesterases (PDEs), which degrade thosenucleotides, and thereby regulate their intracellular concentration,hence their biological effects."

If a person could reach into a cell, and turn the volume of PDE up ordown, he could conceivably control certain vital disease processes inthe human body. Manganiello believes that he may be such a person.

Drugs Are Next Step

After years of PDE research, he said, "we are looking for some helpin learning more about these enzymes from several perspectives,primarily trying to target them in a therapeutically useful fashion."

He and the NHLBI's Technology Transfer Specialist, Lili Portilla,have drawn up an announcement for imminent submission to theFederal Register. It will invite applicants from industry to join in aCooperative Research and Development Agreement (CRADA).

They seek such aid in developing "a specific cyclic nucleotidephosphodiesterase, PDE3. . .as a potential target for therapeuticintervention in diseases of pulmonary, hematologic, cardiovascularand immune systems."

"Phosphodiesterases belong to seven distinct gene families,"Manganiello explained. We are primarily interested in the third one,PDE3. In animal-type or isolated-cell experiments," he added, "plussome information from humans, this enzyme seemed to have somerole in regulation of myocardial contractility, platelet aggregations,airway and vascular smooth-muscle relaxation, insulin secretionstimulation, and perhaps the breakdown of fats and glycogen."

At this stage, he observed, "the payoff would probably bedevelopment of specific drugs or inhibitors, which would alter thoseactivities," presumably for the better.

Manganiello has teased the enzyme's structure apart to the nextmolecular level.

"Within this PDE3 family," he said, "there are at least twosubfamilies, A and B isoforms, which we have cloned and expressed.These forms probably have different tissue distributions, and perhapsdifferent functions. So as far as a commercial venture is concerned, atthis point the payoff would probably be in developing drugs forspecifically altering the functions of these PDE3 A and B enzymes."Equally important, he sees "development of delivery systems to targetspecific cells and tissues."

Immune Cells May Be Key

At the present stage of his research, "such a target would probably bein a circulating immune-system cell, something like a T-lymphocyteor monocyte, in an organ that's relatively easily accessible, such asthe lung." Here he pictures recovery of lavage fluids, andadministration of drugs by inhalation.

"They may be useful," he suggested, "in treating inflammatorydiseases of the lung, such as asthma, or perhaps sarcoidoisis."

Others, he pointed out, "have tried to use inhibitors of this enzymefor certain diseases, and that hasn't worked because of side effects. Idon't think," he added, "that those people tried to develop thesedrugs in conjunction with specific targeting approaches."

His goal, he said, is to "get around the shotgun approach, and try totarget these enzymes in a potentially therapeutically useful fashion."

Research pharmacologist Joseph Beavo, at the University ofWashington, Seattle, told BioWorld Today that Manganiello " did alot of the pioneering work in identifying and characterizing these Aand B isozymes of PDE3. They appear to differ in their regulationphysiologically," Beavo added. "For example, the B forms areregulated by insulin; the A forms probably not."

He observed, "The potential therapeutic applications are many, butthe ones Manganiello is probably dealing with are related to thephysiological functions that these enzymes subserve. For example,inhibitors of PDE3 are being tested as cardiotonic agents. Theyalready are into clinical trials, but fairly controversial [because ofuntoward side effects].

"This enzyme is also potentially useful in platelet diseases, as an anti-thrombotic agent, and as an antihypertensive. About 90 percent ofcurrent R & D in this field focuses on those two applications."

Editor's note: For CRADA information, consult Lili Portilla,technology transfer specialist, NHLBI, (301) 496-4653; for technicalquestions concerning this research, Vincent Manganiello, chairman,Biochemical Physics Section, Pulmonary Care Branch, NHLBI,(301) 496-1770. n

-- David N. Leff Science Editor

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