Over 8 million Americans a year suffer from chronic wounds associated with diabetic ulcers, pressure ulcers, venous stasis ulcers and burns. In many cases the chronic wounds can take years to heal, have a high recurrence rate and for 54,000 patients a year, result in amputations. There are few medications for chronic wounds and none are clearly effective. Maret Pharmaceuticals has shown that angiotensin peptides can rapidly and effectively promote wound healing. They have found that angiotensin II (AII) and angiotensin (1-7) (A1-7) promote tissue regeneration in a number of animal models quicker and more effectively than any other known treatment. A1-7 does not have pressor effects, is non-toxic to animals and will be undergoing clinical safety trials in humans. The objective of this proposal is to develop in vitro screening assays to identify second generation tissue regenerative lead compounds that are more potent, effective and longer acting than A1-7. We will develop assays to measure angiotensin peptide binding to native and recombinant receptors subtypes and functional assays measuring responses to activation of these receptors. We will test a large number of angiotensin analogs we have synthesized for affinity and efficacy at these different receptor subtypes. These compounds will also be tested on in vitro screening assays that measure wound healing capabilities. In future studies (phase II application), promising lead compounds identified in these screening assays will be tested in the same pre-clinical animals studies as we have used for A1-7 to develop more effective and longer acting drugs that can be used to treat individuals with chronic wounds. Furthermore, the screening assays developed in this phase I SBIR proposal will also allow us in future studies to identify non-peptide tissue regenerative drugs that can offer many commercial advantages over the peptide drugs presently available. PROPOSED COMMERCIAL APPLICATIONS: Chronic wounds have a devastating effect on the health and life style of over 8 million Americans a year. The primary pharmacological treatment of diabetic wound healing is the growth factor PDGF (RegranexTM) which was shown to have a 10% improvement over controls and not found to be effective in treating wounds due to pressure ulcers, the largest market for wound healing. Regranex is expensive, costing patients on average $2,000, with total sales of over $80 million in 1999 for its limited therapeutic indications. We anticipate that the market for our angiotensin analogs will be hundreds of millions of dollars a year.