Design and development of a vasoactive intestinal peptide analog as a novel therapeutic for bronchial asthma

Abstract

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.

Generation of Highly Selective VPAC2 Receptor Agonists by High Throughput Mutagenesis of Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Peptide

“…At ϳ50% organic solvent, residues 8 -26 generally adopt a helical structure while the N and C termini remain highly flexible with little discernible structure. VIP analoging based on this structural information and alanine scanning (27) has been directed toward improving peptide stability and potency in BAL fluid for the treatment of asthma (21). Two of these analogs, Ro 25-1392 and Ro 25-1553, were later shown to be VPAC2 selective agonists (18,20).…”

“…VIP chemical analogs Ro 25-1553 and Ro 25-1392 have been reported as VPAC2 selective agonists (18,20), but they were not designed to be selective for VPAC2 so that VPAC2 selective determinants were not known (21). In the current work, we have taken a systematic approach to identify the minimal VPAC2 selective determinants necessary to confer maximal VPAC2 selectivity.…”

Elucidation of Vasoactive Intestinal Peptide Pharmacophore for VPAC1Receptors in Human, Rat, and Guinea Pig

“…VIP also has important growth effects (Muller et al, 1995), effecting the growth of cancers (prostate, lung, pancreatic, breast) (Moody, 1996;Jiang et al, 1997;Moody et al, 1998) as well as normal tissues . Recent reports propose a role of VIP in a number of clinically important areas, including asthma (Bolin et al, 1995); treatment of impotence (Sandhu et al, 1999); pain transmission (Dickinson and Fleetwood-Walker, 1999); pathogenesis of vascular headaches (Edvinsson, 2000); having a neuroprotective effect that could be used to treat Alzheimer's disease or Parkinson's disease (Offen et al, 2000); and having potent anti-inflammatory effects that could be useful in the treatment of septic shock, Crohn's disease, and rheumatoid arthritis (Gomariz et al, 2001;Said, 1996). In addition VIP receptors are highly expressed in a number of cancers, including those of the breast and gastrointestinal tract, and it has been shown these can be used to localize these tumors by imaging methods and, therefore, their presence may be important in various antitumor treatments (Virgolini, 1997).…”

Tuning immune tolerance with vasoactive intestinal peptide: A new therapeutic approach for immune disorders

“…PKA activation can also inhibit both NFκB and MAPK pathways by downregulating TLR and CD14 expression (5). Finally, PKA signaling inhibits Jak-STAT1 pathway and subsequent induction of IRF1 (6). The end result is that the complex of transcriptional transactivators, which were recruited to the promoters of several inflammatory mediators (tumor-necrosis factor-α (TNFα) is shown as an example) in response to the signaling via the TLR4 receptor, is significantly disrupted by neuropeptide treatment (compare profile A with profile B).…”

“…Due to its natural structural conformation, VIP is very unstable and extremely sensitive to the peptidases present in most tissues. Several strategies have been developed to increase VIP half-life such as by the modification and/or substitution of certain aminoacids in the sequence or cycling the structure increases the stability of the peptide [6,52]. Perhaps even more important is work towards improving neuropeptide delivery to target tissues and cells while protecting it against degradation.…”