VIP: A 28-Residue Neuropeptide With Receptors Almost Everywhere

Vasoactive intestinal peptide (VIP) works by activating two class B G protein-coupled receptors, VPAC1 and VPAC2, which it shares with the related peptide PACAP 2. Those receptors are found in the brain, lungs, gut, liver, blood vessels, pancreas and immune cells. So a single 28-residue peptide relaxes smooth muscle, stimulates intestinal secretion, modulates inflammation and synchronises the circadian clock. That breadth is the main reason VIP has been hard to develop. Systemic VIP acts everywhere at once, its plasma lifetime is short 4, and every useful pharmacological tool in the field is itself a peptide 2.

Unlike most compounds in this cluster, VIP is an established endogenous signalling molecule with a large and independent literature. The uncertainty is not whether it does anything. It is whether any of its many actions can be isolated well enough to become a treatment.

Discovery

Sami Said and Viktor Mutt isolated VIP from hog small intestine and reported it in 1970 1. The peptide had potent and varied actions: systemic vasodilation, a fall in blood pressure, increased cardiac output, respiratory stimulation and a rise in blood glucose. It had 28 residues and was chemically distinct from the kinins, substance P, glucagon and secretin. The name reflects where it was found and the first thing it was seen to do. Both turned out to be incomplete. VIP is present in the gut, but it is mainly a neuropeptide, released from nerve endings throughout the peripheral and central nervous systems.

The receptors

VIP belongs to a structurally related superfamily of peptide hormones that includes secretin, glucagon, the glucagon-like peptides, GIP and GHRH 2. Its closest relative is pituitary adenylate cyclase-activating polypeptide (PACAP). The two share three receptors, all class B G protein-coupled receptors. PAC1 is selective for PACAP. VPAC1 and VPAC2 respond to both VIP and PACAP with high affinity 2. Signalling runs mainly through adenylate cyclase and cyclic AMP, although receptor partners can shift that. For example, VPAC1 paired with a receptor-activity-modifying protein shows enhanced phosphoinositide signalling 2.

The two receptors are distributed differently. VPAC1 is widespread in the central nervous system, most abundant in cerebral cortex and hippocampus, and is found peripherally in liver, lung and intestine. VPAC2 messenger RNA is most concentrated in the thalamus and the suprachiasmatic nucleus, the brain's central circadian clock 2. Because VIP itself does not discriminate much between them, the native peptide cannot target one system without affecting the other.

How a class B receptor reads the peptide

Class B receptors bind their peptide ligands in two steps, and VIP follows the pattern. The large N-terminal extracellular domain of the receptor captures the C-terminal, largely helical part of the peptide. This contributes most of the binding affinity. The peptide's N-terminal residues are then positioned inside the transmembrane core, where they trigger the conformational change that activates the G protein. Affinity and activation therefore depend on different ends of the molecule.

That division explains how the field has built tools. Changes to the N-terminus can turn an agonist into an antagonist while keeping binding, because the peptide still docks but no longer activates. Substitutions along the helical C-terminal region change which receptor the peptide prefers. The VPAC1-selective and VPAC2-selective analogues used in research were made this way, one residue at a time 2. It also explains the limit the IUPHAR review describes. Every selective tool is a modified version of a peptide of about 28 residues, with the same clearance and delivery problems as the parent 2.

The shared receptors complicate interpretation too. VIP and PACAP act at the same VPAC receptors with similar affinity, so deleting the VIP gene in a mouse removes one ligand while leaving the other. Phenotypes in VIP-deficient animals show what VIP contributes that PACAP cannot replace, which is not the same as everything VIP does. The same caution applies in reverse to receptor-deletion studies, which remove the response to both peptides.

Roles across systems

The circadian role is the clearest demonstration from animal genetics. Mice lacking VIP show a severely disrupted circadian phenotype 2, consistent with VIP's role in coupling the individual clock neurones of the suprachiasmatic nucleus into a coherent rhythm. This is rodent evidence, but of the strongest kind: remove the gene and the function fails.

The immune role is more complicated than its reputation. VIP is widely described as anti-inflammatory, and in cell culture and many rodent models it suppresses inflammatory cytokines and promotes regulatory T cells. Yet VIP-deficient mice were paradoxically resistant to experimental autoimmune encephalomyelitis, with inflammatory cells failing to enter the nervous system 2. The same molecule appears to restrain inflammation in some settings and to be needed for it in others. That is a warning against summarising VIP as simply immunosuppressive.

The secretory role is shown most dramatically in humans. In 1958 Verner and Morrison described patients with pancreatic islet cell tumours, refractory watery diarrhoea and low blood potassium 3. That was twelve years before VIP was isolated. Tumour secretion of VIP was later identified as the cause, and such tumours are now called VIPomas. Uncontrolled release of this one peptide is enough to drive life-threatening fluid loss from the intestine.

In the pancreas, VIP acting at VPAC2 stimulates glucose-dependent insulin secretion and promotes beta-cell proliferation in experimental systems. Because native VIP is short-lived and acts widely, the metabolic interest has shifted to VPAC2-selective agonists, which remain at the preclinical and early development stage 4.

Why it has been hard to develop

Three obstacles recur. The first is clearance. Native VIP has a short plasma half-life, cleared by peptidases within minutes 4. The second is breadth. A systemic concentration high enough to act on one target will also dilate blood vessels and lower blood pressure, the very effects that gave the peptide its name 1. The third is the toolbox. The IUPHAR review identified the main impediment to translational research as the fact that all the useful pharmacological tools for these receptors are peptides 2. There are no well-characterised small-molecule agonists or antagonists to separate VPAC1 from VPAC2 effects in vivo.

The strategies that have reached patients get around the breadth problem by delivering VIP locally, not by making a better molecule. The alternative, a receptor-selective analogue stable enough for systemic use, is the approach the metabolic programmes have pursued 4. It asks the chemistry to solve three problems at once: selectivity between two closely related receptors, resistance to peptidases, and enough duration to be practical. Each has been solved separately for other peptide classes. Solving all three together for VIP has not yet produced an approved drug. The distinction between evidence types matters here as well. Most of the case for selective agonists rests on rodent and cell-culture data, not on human trials of those molecules.

The approved use and the clinical trials

Aviptadil is synthetic VIP. Its one licensed use is in a fixed combination with the alpha-blocker phentolamine, given by intracavernosal injection for erectile dysfunction. In clinical studies the combination was effective in at least 80 percent of men, including men who had not responded to other treatments, with little injection pain and negligible risk of priapism 5. Local injection confines VIP's vasodilator action to the target tissue.

Inhalation is the other local route. In an open-label phase II study, 20 patients with active pulmonary sarcoidosis inhaled nebulised VIP for four weeks. Cells recovered by bronchoalveolar lavage produced less tumour necrosis factor-alpha, and regulatory T cells increased. In vitro, VIP converted naive CD4 T cells into FoxP3-expressing regulatory T cells 6. The study had no control group. It shows a biological effect in human lungs, not a clinical benefit.

The largest controlled test of systemic VIP was negative. TESICO randomised patients with COVID-19-associated acute hypoxaemic respiratory failure at 28 US sites to intravenous aviptadil or placebo, alongside a separate remdesivir comparison 7. Among 461 participants in the aviptadil analysis, the odds ratio for a better recovery status at day 90 was 1.11 (95% CI 0.80 to 1.55), which is not significant. Mortality at 90 days was 38 percent with aviptadil and 36 percent with placebo. Serious adverse events by day 5 occurred in 63 percent versus 56 percent. The rationale had come from nonclinical studies of surfactant production, cytokine suppression and viral replication in lung cells 7. It did not survive a properly powered trial.

The fair summary

VIP is one of the better-understood peptides covered in this cluster. Its receptors are cloned and classified 2, its physiological roles are supported by gene-deletion studies in mice, and its secretory power is plain from human disease 3. What it lacks is a way to act on one of those roles without triggering the rest. The successful clinical use relies on local injection 5. The most rigorous systemic trial was negative 7. Receptor-selective analogues remain the likeliest route forward 4, and they have not yet reached the clinic.