Congestive heart failure is the only cardiovascular disease that is increasing in prevalence. It is a common cause of death, is accompanied by high indirect costs for treatment, and has a low survival rate upon its onset. The long term goal of this proposal is to develop an orally available drug based on an endogenous peptide to be useful in the treatment of congestive heart failure (CHF). The proposal suggests that a conjugated hBNP may be able to induce the cardiovascular, renal, and endocrine effects that are associated with the native peptide. The most notable advantage of dosing an hBNP conjugate over the native peptide is oral delivery. Covalent attachment of amphiphilic oligomers affords protection from degradative enzymes and facilitates delivery into systemic circulation through the gut wall. The specific aims of this proposal are to synthesize hBNP amphiphilic polymer conjugates, test the conjugates for agonist activity at the human natriuretic peptide receptor A (NPR-A) in vitro, test the conjugates for increased resistance to proteases, and test the conjugates for oral bioavailability in mice. We propose that an oral hBNP conjugate will expand the utilization of this therapeutic to individuals suffering from early stage to overt CHF. Furthermore, an oral hBNP conjugate, by preventing progression from early stage heart failure to more severe phases, may significantly reduce medical costs associated with the treatment of CHF. This Phase I proposal describes a strategy testing three classes of oligomers in order to find the optimal conjugate. Phase II studies will involve pharmacokinetic and pharmacodynamic studies of the most promising candidates arising from Phase I studies
