Vasoactive Intestinal Peptide (VIP)

What Is Vasoactive Intestinal Peptide (VIP)?

Vasoactive intestinal peptide (VIP) is a 28-amino-acid neuropeptide that works both as a gut peptide hormone and as a neurotransmitter. It was first reported as a vasodilator in 1970 ^[1], and its actions are mediated through two receptors, VPAC1 and VPAC2 ^[2].

Research has linked VIP to neuronal, epithelial, and endocrine cell functions that regulate ion secretion, nutrient absorption, gut motility, glycemic control, immune responses, and circadian rhythms ^[1]. VIP is also made by immune cells. Thymocytes produce and secrete it, and lymphocytes increase VIP production when exposed to proinflammatory cytokines such as IL-1, IL-6, and TNF-alpha ^[3].

Synthetic VIP carries the nonproprietary name aviptadil. It has been studied as an intravenous drug in COVID-19 respiratory failure ^[4] and, combined with the adrenergic drug phentolamine, as an injectable treatment candidate for erectile dysfunction ^[5].

Chemical Structure and Molecular Identity

VIP is a linear 28-residue peptide that begins with histidine and ends with asparagine; in its native form the C-terminal asparagine is amidated. The PubChem record indexed as aviptadil (CID 16132300) lists the molecular formula C147H237N43O43S and a molecular weight of 3326.8 g/mol, with CAS number 40077-57-4.

The PubChem structure depicts a free C-terminal carboxylic acid. The amidated peptide differs only by an amino group in place of that terminal hydroxyl, which gives the formula C147H238N44O42S. Researchers comparing certificates of analysis against reference data should check which C-terminal form a given record describes.

Alanine and D-amino acid scanning has mapped which residues matter for receptor binding. For human VPAC2, the backbone or side-chain orientations of Asp3, Phe6, Thr7, Tyr10, Arg12, Tyr22, and Leu23 were most important for high-affinity potency, while the side chains of Ser2, Asp8, Asn9, Gln16, Val19, Lys20, Lys21, Asn24, and Ser25 were not essential ^[2].

Research History and Development

VIP moved from a gut peptide first reported as a vasodilator in 1970 to a drug candidate tested in erectile dysfunction and, later, acute respiratory failure ^[1]. Studies of genetically engineered mice lacking VIP or its receptors have since been used to probe its normal physiological roles ^[1].

Erectile dysfunction program. An injectable formulation of aviptadil combined with phentolamine was submitted for marketing authorization in several countries beginning in 1997 and had been approved in New Zealand by April 2000 ^[5]. Clinical trials of that program were placed on hold in August 1999 after US regulators raised safety concerns about a competitor’s phentolamine product ^[5]. A 2019 systematic review of intracavernosal injectables noted that the aviptadil/phentolamine combination had been approved in only a few geographic regions ^[6].

Respiratory program. A patented VIP formulation designated RLF-100 received US Orphan Drug Designation in 2001 for acute respiratory distress syndrome (ARDS) and in 2005 for pulmonary arterial hypertension ^[7]. During the COVID-19 pandemic, aviptadil was evaluated in a multicenter randomized controlled trial in critical COVID-19 respiratory failure ^[4], and a 2025 meta-analysis pooled the available ARDS evidence ^[8].

Mechanisms Studied in Research

VIP acts mainly through the VPAC1 and VPAC2 receptors, and it shares this receptor system with the related peptide PACAP, which also binds a third receptor, PAC1 ^[9]. Mechanistic research has focused on receptor pharmacology, immune signaling, lung biology, and tumor biology.

Receptor pharmacology

Comparison of VPAC1 and VPAC2 showed that the side chains of Thr7, Tyr10, Thr11, and Tyr22 were much more critical for high affinity at human VPAC2 than at VPAC1, whereas the orientation of Asn24 mattered more for VPAC1 ^[2]. The same study found significant species differences and differences between expression systems, which the authors flagged as important for designing receptor-selective analogs ^[2].

Immune signaling

VIP has been described as a potent anti-inflammatory factor produced by lymphoid cells ^[7]. In murine thymocytes, VIP1 and VIP2 receptor mRNA was detected, and VIP affected cytokine production, cell mobility, and apoptosis ^[3]. Reviews have discussed its effects in autoimmune and inflammatory disorders such as rheumatoid arthritis ^[10].

Lung and tumor biology

Nonclinical studies cited by trial investigators report that VIP upregulates surfactant production, inhibits cytokine synthesis, prevents cytopathy, and blocks SARS-CoV-2 replication in pulmonary cells ^[4]. In oncology, VPAC1, VPAC2, and PAC1 are overexpressed on several common tumors, including breast, lung, prostate, central nervous system tumors, and neuroblastoma; this has been explored for tumor imaging and for delivering cytotoxic agents coupled to VIP/PACAP analogs ^[9].

Key Findings From Published Studies

The strongest human evidence comes from trials in respiratory failure, where aviptadil did not meet its primary endpoint and pooled data show no clear survival benefit. Other findings come from cell studies and reviews.

Randomized trial in COVID-19 respiratory failure

In a multicenter, placebo-controlled trial at ten US hospitals, 196 patients with COVID-19 respiratory failure were randomized 2:1 to intravenous aviptadil or placebo ^[4]. The primary endpoint, being alive and free from respiratory failure at day 60, did not reach statistical significance (odds ratio 1.6; 95% CI 0.86 to 3.11) ^[4]. The investigators reported a two-fold odds of survival at day 60 (OR 2.0; 95% CI 1.1 to 3.9; p = 0.035), improvement in respiratory distress ratio, and reduced interleukin-6 release by day 3 ^[4]. Subgroup analyses suggested larger effects in patients on high-flow nasal oxygen at baseline and in mechanically ventilated patients, but the authors concluded the primary analysis showed no difference from placebo ^[4].

Meta-analysis in ARDS

A 2025 systematic review included nine studies (two randomized trials and seven case series) covering 665 patients, 361 of whom received aviptadil ^[8]. In the two randomized trials, the survival odds ratio versus placebo was 1.01 (95% CI 0.72 to 1.42; p = 0.93), indicating no significant benefit. The uncontrolled case series reported 48 of 54 patients surviving, with improvements in oxygenation and inflammatory markers ^[8].

Laboratory findings

• Receptor-scanning studies in cell lines identified the residues driving VPAC2 versus VPAC1 affinity ^[2].
• Murine thymocyte studies showed VIP production rising after stimulation with concanavalin A, LPS, or anti-TCR antibody ^[3].
• VIP/PACAP showed prominent growth effects on several tumor types expressing their receptors, with signaling involving transactivation of the epidermal growth factor receptor family ^[9].

Because native VIP is amidated while some reference records depict the free acid, HPLC and mass-spectrometry data on a certificate of analysis help confirm identity.

Regulatory and Research Status

Aviptadil is not approved by the US Food and Drug Administration for any indication. It holds US orphan drug designations for ARDS (2001) and pulmonary arterial hypertension (2005) ^[7].

Outside the United States, an aviptadil/phentolamine combination for erectile dysfunction has been approved in a small number of countries, including New Zealand ^[5][6]. In respiratory disease, the published randomized evidence has not shown a significant effect on its primary or pooled survival endpoints ^[4][8], and reviewers have called for larger, well-designed trials ^[8].

Research use of VIP spans receptor pharmacology, neuroimmunology, gastrointestinal physiology, and oncology, where receptor overexpression on tumors remains an active area for imaging and targeted delivery ^[9][1].