This application concerns plasminogen activation, a widespread mechanism for producing pericellular proteolysis that is integral to numerous physiological and pathological processes. At present plasminogen activation can be manipulated in vivo for therapeutic purposes only by acute resort to rather crude measures, namely, intravascular injection of plasminogen activators (PA) and/or inhibitors of plasmin or PAs. In more ideal circumstances a therapist should ultimately enjoy access to medications allowing production and removal of plasmin to be controlled reliably, reproducibly, inexpensively, and for any desired time interval. The studies proposed here will not provide such medications; they are intended, rather, to be a first step - to yield basic information which, in the era of computer-assisted drug design, might in due course permit envisaging simpler structures than those now available for modulating plasminogen activation in vivo. To this end a program has been launched to acquire information on plasminogen structure and activity, of the kind ultimately needed as a foundation for contemplating rational intervention in the functioning of the fibrinolytic system in vivo. Based on the data obtained so far, (summarized in subsequent sections; cf. also Appendices) an initial, incomplete but tantalizing profile of several structure-activity parameters can be drawn, and a rational further pursuit of the investigation would be greatly stimulated by the availability of more refined and detailed structural information. For this purpose it is proposed now to initiate, during a sabbatical leave, the study of a series of truncated plasminogens by fluorescence spectroscopy and x-ray crystallography.
