Biological functions of vasoactive intestinal peptide (VIP) in respiratory system and potential clinical application

In a respiratory system, VIP acts as neurotransmitter or neuromodulator of the inhibitory non-adrenergic and non-cholinergic nervous system and influences many aspects of pulmonary biology. A clinical application of VIP is believed to offer potential benefits in the treatment of chronic inflammatory lung diseases, because of its attractive biological functions including anti-inflammation and bronchodilation. In this investigation, development of efficacious VIP derivatives and drug delivery systems was attempted for the potential application of VIPs for treatment of asthma/chronic obstructive pulmonary disease (COPD). VIP and derivatives were chemically synthesized, and their solution structures were evaluated by circular dichroic and NMR spectral analyses. In addition, several biological functions of VIPs, including stimulation of protein kinases, receptor binding, relaxant effects on smooth muscle, protective effects on cigarette smoke-induced apoptotic cell death, were also investigated. On the basis of chemical modification studies, potent VIP receptor agonists, including [R (15,20,21), L (17)]-VIP-GRR (IK312532) and [R (15,20,21), L (17), A (24,25), des-N-28]-VIP-GRR (IK312548), were successfully developed. They showed long-lasting bronchodilation and anti-apoptotic effects via deactivation of caspase-3 and matrix metalloprotease.