The first ACE inhibitors were developed by D W Cushman and M A Ondetti at the Squibb Corporation following extensive work on factors isolated from the Brazilian arrowhead viper Bothrops jaracusa. These small peptides were noticed because of their ability to prolong the action of the local hormone, bradykinin, which also dilates blood vessels. Many years of work were needed to find suitable analogues of the natural peptides and to demonstrate their safety and effectiveness. However, a valuable new type of therapy was established by developing the leads provided by the natural toxin. A more recent example involving snake venoms concerns inhibitors of platelet aggregation and blood clotting.
Many snake venoms have powerful anticoagulant or procoagulant activities.
6 Much of this activity is associated with high molecular weight enzymes, but smaller active molecules have also been characterised. By binding to this receptor, they prevent the interaction between platelets and fibrinogen. The 3-dimensional structure of one of these antagonists has been determined by nuclear magnetic resonance. With an understanding of the shape of the functional site on the snake venom protein, workers at Genentech have been designing small, peptide-mimicking molecules that could be used as drugs to control abnormal clotting. Future developments from snake toxins A more speculative example relates to drug design based on a group of protein toxins, called dendrotoxins.