EXPRESSION OF HUMAN RENIN FROM CLONED GENES

HYPERTENSION IS A SERIOUS AND WIDESPREAD MEDICAL PROBLEM. WHILE A VARIETY OF APPROACHES CURRENTLY EXIST FOR CONTROLLING HYPERTENSION, MANY PATIENTS COULD BENEFIT FROM NEW ANTIHYPERTENSIVE DRUGS THAT ARE MORE SPECIFIC THAN THOSE PRESENTLY AVAILABLE. RENIN INHIBITORS CONSTITUTE A POTENTIAL CLASS OF HIGHLY ACTIVE YET SPECIFIC ANTIHYPERTENSIVE AGENTS. ONE IMPEDIMENT TO THE DESIGN OF USEFUL RENIN INHIBITORS IS THE LACK OF DETAILED INFORMATION CONCERNING THE STRUCTURE OF THE ENZYME. PURE HUMAN RENIN IS VERY DIFFICULT TO OBTAIN AND, AS YET, NO 3-DIMENSIONAL CRYSTALLOGRAPHIC ANALYSIS HAS BEEN PERFORMED. IT IS PROPOSED TO USE CDNA AND GENOMIC CLONES CODING FOR HUMAN RENIN TO PRODUCE THE ENZYME IN QUANTITIES SUFFICIENT FOR ESTABLISHING ITS CRYSTAL STRUCTURE. CONSTRUCTIONS ARE PROPOSED FOR THE SYNTHESIS OF BOTH PRORENIN AND MATURE RENIN IN MAMMALIAN CELLS AND FOR MATURE RENIN IN BACTERIA. IT IS PROPOSED THAT IN PHASE I, APPROPRIATE CONSTRUCTIONS WILL BE MADE AND THAT CONDITIONS WILL BE ESTABLISHED FOR OBTAINING THE DESIRED EXPRESSED PRODUCTS. PHASE II WILL ENCOMPASS THE LARGER SCALE PRODUCTION AND PURIFICATION OF THE ENZYME. THE AVAILABILITY OF LARGE AMOUNTS OF PURE HUMAN RENIN WILL ALLOW STRUCTURAL STUDIES TO BE PERFORMED AS WELL AS THE DIRECT ASSESSMENT OF THE ACTIVITY OF NEWLY SYNTHESIZED RENIN INHIBITORS.