Before a leech starts sucking blood, its sharp triple-jawed teeth pierce aneat Y-shaped incision in the victim's skin. Into this wound its salivaryglands squirt a cocktail of proteins that make the process painless,expand the local blood-vessels and prevent the blood from clotting atthe open cut.After this anesthesia, vasodilation and anti-coagulation prepping, theleech begins serious blood aspiration. In this process, which can takehours, its body may swell to 10 times normal size with ingested blood,and that single stored sanguine meal can take it months to digest.In past centuries, when pre-scientific medical practice relied largely onbalancing the four bodily "humours" _ black bile, yellow bile, phlegmand blood _ the European leech, Hirudo medicinalis, was a ready-made blood-letting device for rendering a patient less "plethoric."Tumors, skin diseases, gout, whooping cough, mental illness andheadache were among the ailments for which doctors prescribedleeching, right through the 19th century. Now in the 20th, leeches aremuch used in reconstructive microsurgery. They aid tissue drainageand increase blood circulation through the micro-sutures.Hirudin is the key protein that the European leech injects to stopsucked blood from clotting. Its recombinant analog, Hirulog, wasdeveloped at Cambridge, Mass.-based Biogen Inc. by the firm'sdirector of biological research, John Maraganore. It is now in extensiveclinical trials as an anticoagulant. (See BioWorld Today, March 15,1994, p. 2.)One multi-center Phase III study, Maraganore told BioWorld Today,testing the drug in several thousand angioplasty patients, is nownearing completion.In shed blood, hirudin blocks formation of thrombin, an enzyme thatconverts fibrinogen to fibrin, early in the clotting cascade. Decorsin,from saliva of the North American leech, Macrobdellae decora, inhibitsplatelet aggregation, downstream from thrombin. Farther upstream inthe coagulation process, antistasin, from a Mexican leech, checksFactor X, which converts prothrombin to thrombin.And that's not all. To the recently discovered leech-saliva anti-clottingproteins add "kistin, omatin, ornatin and others," said Andrzej Krezel, apost-doctoral fellow in the nuclear magnetic resonance (NMR)structural group headed by Gerhard Wagner at Harvard MedicalSchool. "The number of leech anti-hemostatic proteins has grown fromone, hirudin, to five or six, with many more to come in the near future,it's going to be a fairly large family of proteins, Krezel told BioWorldToday.Analyzing the three-dimensional structures of these molecules byNMR, Krezel and Wagner asked themselves whether all members ofthe growing family might share a common feature of moleculararchitecture, a tertiary fold. They are co-authors of a paper in today'sissue of Science, titled: "Structure of the RGD Protein Decorsin:Conserved Motif and Distinct Function in Leech Proteins That AffectBlood Clotting."(RGD denotes the trio of amino acids, Arginine-Glycine-Aspartic Acid,that seems to be a common denominator in the leech proteins'sequence, and clue to their structure.)"We were the ones who discovered decorsin five or six years ago," saidbiochemist Robert Lazarus, head of protein engineering at GenentechInc. "Nobody had ever described a platelet aggregation inhibitor from aleech before," he told BioWorld Today, "so once we had screened abunch of leeches for anti-clotting activity, found, purified and clonedthe protein sequences, and characterized how it binds its receptor, weinitiated a collaboration with Wagner at Harvard, to determine, byNMR, decorsin's structural conformation."Biogen did similar NMR studies of its hirudin analog, Hirulog, in thelate 1980s, Maraganore said, but has not published the findings.Commenting on the Genentech report in Science, he said, "Thecomponent of decorsin that's interesting is the Arg-Gly-Asp sequenceand related molecular architecture, which gives it a high-affinitybinding to the glycoprotein receptor on the platelet surface."He explained that knowing enough about the architecture of that regionmakes possible mimicking the epitope's effect by synthesizing a smallpeptide. "That effectively is what we've done with Hirulog,"Maraganore added, "which is of course a derivative of hirudin."Thus, he pointed out, South San Francisco-based Genentech "might beable now to mimic the structure of decorsin with a smaller peptidebased on the orientation of that Arg-Gly-Asp sequence." He added,"Clearly, decorsin may have independent applications as a componentof antithrombotic therapy."But Genentech's Lazarus said, "I don't think this protein per se will bea product. At this point it and other leech proteins are being used astools for developing small molecules as more potent and selectiveinhibitors."Among companies furthest along in making peptide-mimicking drugsbased on the Arg-Gly-Asp sequence are COR Therapeutics Inc., Merck& Co., Roche Holding Ltd., GD Searle & Co., SmithKline Beechamplc and Telios Pharmaceuticals Inc., according to Maraganore. "It'sreally a very crowded field," he observed.As for the leech's pain-killing and vasodilating foreplay, Maraganoresurmises that these effects may be in some way, "yet to be discovered,"side-effects of its clot-blocking protein action. n
-- David N. Leff Science Editor
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