DESIGN AND DEVELOPMENT OF A VASOACTIVE-INTESTINAL-PEPTIDE ANALOG AS ANOVEL THERAPEUTIC FOR BRONCHIAL-ASTHMA

Analogs of vasoactive intestinal peptide (VIP) were synthesized and sc reened as bronchodilators with the ultimate goal of enhancing the pote ncy and extending the duration of action of the native peptide. Severa l design approaches were applied to the problem. First, the amino acid residues required for receptor binding and activation were identified . A model of the active pharmacophore was developed. With knowledge of the secondary structure (NMR) of the peptide, various analogs were sy nthesized to stabilize alpha-helical conformations. Having achieved a level of enhanced bronchodilator potency, our approach then concentrat ed on identification of the sites of proteolytic degradation and synth esis of metabolically-stable analogs. Two primary cleavage sites on th e VIP molecule were identified as the amide bonds between Ser(25)-Ile( 26) and Thr(7)-Asp(8). This information was used to synthesize cyclic peptides which incorporated disulfide and lactam ring structures. Anal og work combined the best multiple-substitution sites with potent cycl ic compounds which resulted in identification of a cyclic lead peptide . This compound, Ro 25-1553, exhibited exceptionally high potency, met abolic stability, and a long duration of action and may be an effectiv e therapeutic for the treatment of bronchospastic diseases. (C) 1995 J ohn Wiley and Sons, Inc.