PROTEIN CRYSTALLOGRAPHY AND INFECTIOUS-DISEASES

The current rapid growth in the number of known 3-dimensional protein structures is producing a database of structures that is increasingly useful as a starting point for the development of new medically releva nt molecules such as drugs, therapeutic proteins, and vaccines. This d evelopment is beautifully illustrated in the recent book, Protein stru cture: New approaches to disease and therapy (Perutz, 1992). There is a great and growing promise for the design of molecules for the treatm ent or prevention of a wide variety of diseases, an endeavor made poss ible by the insights derived from the structure and function of crucia l proteins from pathogenic organisms and from man. We present here 2 i llustrations of structure-based drug design. The first is the prospect of developing antitrypanosomal drugs based on crystallographic, ligan d-binding, and molecular modeling studies of glycolytic glycosomal enz ymes from Trypanosomatidae. These unicellular organisms are responsibl e for several tropical diseases, including African and American trypan osomiases, as well as various forms of leishmaniasis. Because the targ et enzymes are also present in the human host, this project is a pione ering study in selective design. The second illustrative case is the p rospect of designing anti-cholera drugs based on detailed analysis of the structure of cholera toxin and the closely related Escherichia coi l heat-labile enterotoxin. Such potential drugs can be targeted either at inhibiting the toxin's receptor binding site or at blocking the to xin's intracellular catalytic activity. Study of the Vibrio cholerae a nd E. coil toxins serves at the same time as an example of a general a pproach to structure-based vaccine design. These toxins exhibit a rema rkable ability to stimulate the mucosal immune system, and early resul ts have suggested that this property can be maintained by engineered f usion proteins based on the native toxin structure. The challenge is t hus to incorporate selected epitopes from foreign pathogens into the n ative framework of the toxin such that crucial features of both the ep itope and the toxin are maintained. That is, the modified toxin must c ontinue to evoke a strong mucosal immune response, and this response m ust be directed against an epitope conformation characteristic of the original pathogen.