Design and development of a vasoactive intestinal peptide analog as a novel therapeutic for bronchial asthma.
Analogs of vasoactive intestinal peptide (VIP) were synthesized and screened as bronchodilators with the ultimate goal of enhancing the potency and extending the duration of action of the native peptide. Several 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 synthesized to stabilize alpha-helical conformations. Having achieved a level of enhanced bronchodilator potency, our approach then concentrated on identification of the sites of proteolytic degradation and synthesis of metabolically-stable analogs. Two primary cleavage sites on the VIP molecule were identified as the amide bonds between Ser25-Ile26 and Thr7-Asp8. This information was used to synthesize cyclic peptides which incorporated disulfide and lactam ring structures. Analog work combined the best multiple-substitution sites with potent cyclic compounds which resulted in identification of a cyclic lead peptide. This compound, Ro 25-1553, exhibited exceptionally high potency, metabolic stability, and a long duration of action and may be an effective therapeutic for the treatment of bronchospastic diseases.
Bolin
D R
DR
Roche Research Center, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110.
Michalewsky
J
J
Wasserman
M A
MA
O'Donnell
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D015195:Drug Design; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use
D014660:Vasoactive Intestinal Peptide