VIP 10mg Peptide

VIP is a 28-residue neuropeptide, His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn, carried at residues 125 to 152 of the 170-residue prepro-VIP precursor catalogued in UniProt as P01282. Sami Said and Viktor Mutt isolated it from hog small intestine and reported it in Science in 1970, describing a polypeptide that produced systemic vasodilation, hypotension, increased cardiac output, respiratory stimulation and hyperglycaemia, and that was chemically distinct from the kinins, substance P, glucagon and secretin. The name records the assay it was found in rather than the biology it turned out to govern.

Sequence comparison later placed VIP in the secretin/glucagon superfamily alongside secretin, glucagon, GHRH, PACAP and the peptide histidine methionine PHM-27, which is encoded on the same precursor at residues 81 to 107 and released from the same prohormone. Both peptides are alpha-amidated at their C-terminus by the peptidylglycine alpha-amidating monooxygenase system, a two-enzyme sequence encoded in a single transcript. For VIP the amidated residue is Asn28, and the amide is not a chemical footnote: it is part of what the receptor binding pocket reads.

The molecule is unusually widely distributed. It is a transmitter in the enteric nervous system, a vasodilator in the pulmonary and systemic circulation, a secretagogue in the gut epithelium, an immune modulator on T cells and macrophages, and the coupling signal that holds the roughly 20,000 neuronal clocks of the suprachiasmatic nucleus in phase with one another. That breadth means the experimental context, not the molecule, decides which receptor and which downstream pathway dominates a given result. The single constraint every VIP experiment shares is speed of clearance: infused intravenously in healthy volunteers, plasma VIP fell by first-order kinetics with an average disappearance half-time of about one minute.

VIP acts on two class B G protein-coupled receptors, VPAC1 (gene VIPR1) and VPAC2 (gene VIPR2). Both bind VIP and PACAP with comparable affinity, which is why receptor-level attribution in VIP experiments usually requires a knockout, a selective agonist or an antagonist rather than ligand concentration alone. A third receptor in the family, PAC1, prefers PACAP by more than two orders of magnitude and is not a principal VIP target. VPAC1 dominates in lung epithelium, liver, intestinal mucosa and on T cells; VPAC2 dominates in smooth muscle, the suprachiasmatic nucleus and pancreatic islets.

Both VPAC receptors couple to Gs. Occupancy activates adenylyl cyclase, raises intracellular cAMP and activates protein kinase A, which is the common step behind the vasodilation, bronchodilation, intestinal water and electrolyte secretion, and transcriptional effects that follow. The cryo-EM structure of the human VIP1 receptor bound to PACAP27 and a Gs heterotrimer, solved by Duan and colleagues in 2020 using a NanoBiT tethering strategy to stabilise the complex, showed the ligand N-terminus inserting into the pocket formed by the transmembrane bundle while the C-terminal half is held by the extracellular domain. That two-domain arrangement explains why truncating VIP at either end costs potency for different reasons.

Downstream of cAMP, the immunological arm of VIP pharmacology runs through inhibition of NF-kappaB nuclear translocation in activated macrophages and dendritic cells, with reduced transcription of TNF-alpha, IL-6 and IL-12, and through a separate effect on T cell fate that favours CD4+CD25+Foxp3+ regulatory T cells over Th1 and Th17 differentiation. The two arms are separable: the vasodilator effect appears within seconds of exposure and disappears as fast, while the transcriptional effects need hours and outlast the peptide by days.

Clearance is the mechanistic fact that shapes every study design around this molecule. In four healthy volunteers given graded intravenous infusions of 0.6, 1.3 and 3.3 pmol/kg/min over 30-minute periods, Domschke and colleagues measured an apparent metabolic clearance rate of about 9 mL/kg/min and an apparent volume of distribution of about 14 mL/kg. Neutral endopeptidase 24.11 on the airway surface degrades inhaled VIP quickly enough that co-application of the NEP inhibitor thiorphan measurably prolongs its haemodynamic effect in the isolated rabbit lung.

Said and Mutt were fractionating hog small intestine looking for a vasodilator when they isolated the peptide that became VIP, and they published it in Science in 1970 as a polypeptide with potent and diverse biological action: systemic vasodilation, hypotension, increased cardiac output, respiratory stimulation and hyperglycaemia, chemically distinct from the kinins, substance P, glucagon and secretin. The name has stuck for fifty-five years, and it is a poor description of what the molecule mostly does. VIP is principally a neuropeptide. Its intestinal abundance reflects the density of enteric neurons, not an endocrine role in the gut wall.

The gene structure explains a second common confusion. Prepro-VIP is a 170-residue precursor that yields two amidated bioactive peptides from the same processing event: PHM-27 at residues 81 to 107 and VIP at residues 125 to 152. Because both come out of the same prohormone, a genetic knockout of the VIP locus removes PHM as well, which is why the 2003 Colwell study is titled for VIP- and PHI-deficient mice rather than for VIP alone. Any circadian or immune phenotype from that line is formally attributable to the pair, and the receptor-level work with Vipr2-/- animals is what separates them.

Human and porcine VIP have the same 28-residue sequence, which is why the original hog-derived peptide could be carried directly into human physiology work and why PubChem's aviptadil record still lists porcine vasoactive intestinal octacosapeptide among its synonyms. That conservation is not universal in the family: chicken and frog VIP differ at several positions, so cross-species work needs the source species named.

The circadian work is the strongest and most replicated part of the VIP literature, and it is close to absent from how the compound is usually described. The suprachiasmatic nucleus contains roughly 20,000 neurons, each of which carries an autonomous transcriptional clock. The organism-level rhythm is not the sum of those clocks; it is what emerges when they hold phase with one another. VIP is the coupling signal that makes that happen, and VPAC2 is the receptor that reads it.

The evidence arrived in a tight sequence. Shen and colleagues (2000) overexpressed the human VPAC2 receptor in the mouse suprachiasmatic nucleus from a YAC transgene and got animals that re-entrained faster to a phase advance and ran significantly shorter free periods in constant darkness. Harmar and colleagues (2002) deleted the receptor and got the opposite extreme: Vipr2-/- mice lost behavioural rhythmicity in constant darkness while still masking normally to light, and their suprachiasmatic neurons showed flat expression of Per1, Per2, Cry1 and arginine vasopressin. Microinjected VIP restored circadian gene expression in mutant slices.

Colwell and colleagues (2003) characterised the ligand-side knockout: VIP/PHI-deficient mice were normal under a light-dark cycle but in constant darkness began activity roughly eight hours early, ran shortened free periods, lost rhythm coherence, and about a quarter became frankly arrhythmic. Aton and colleagues (2005) then separated the two contributions with single-cell recording, showing that loss of VIP or VPAC2 abolished firing rhythms in about half of suprachiasmatic neurons and desynchronised the rest, and that a VPAC2 agonist rescued Vip-/- but not Vipr2-/- slices. Maywood and colleagues (2006) closed the loop with real-time imaging: depolarisation and gastrin-releasing peptide can transiently resynchronise Vipr2-/- cells, but the synchrony collapses again without VIP signalling.

The consequences reach past locomotor activity. Sheward and colleagues (2007) found that Vipr2-/- mice lacked circadian rhythms of wheel running and corticosterone but retained strongly rhythmic hepatic clock gene expression and could still be entrained by restricted feeding, which is a clean demonstration that food is a zeitgeber capable of coordinating peripheral clocks even without a functioning central pacemaker. More recent work in Science (2026) traced a rhythmic circuit from suprachiasmatic VIP neurons through the paraventricular nucleus to the ventrolateral periaqueductal grey that sets daily variation in nociceptive threshold in a mouse neuropathic pain model.

Petkov and colleagues (Journal of Clinical Investigation, 2003) reported that VIP is deficient in serum and lung tissue from patients with primary pulmonary hypertension, shown by radioimmunoassay and immunohistochemistry, and that the corresponding receptors are upregulated on Northern blot, Western blot and immunostaining. In eight patients, supplying the peptide lowered mean pulmonary artery pressure and raised cardiac output and mixed venous oxygen saturation. The study was small and open, and it set the agenda for everything that followed.

The genetic complement came four years later. Said and colleagues (Circulation, 2007) showed that VIP-/- mice breathing room air spontaneously develop moderate right ventricular hypertension with right ventricular hypertrophy, enlarged and thickened pulmonary arteries, increased muscularisation of small branches with narrowed lumen, and perivascular inflammatory infiltrates, in the absence of systemic hypertension or arterial hypoxaemia. Mortality was increased. Four weeks of VIP attenuated both vascular and ventricular remodelling. Hamidi and colleagues (2011) extended this to the monocrotaline rat, where VIP started at the same time as monocrotaline almost entirely prevented the pathology, VIP started three weeks later only partially reversed it, and combining VIP with the endothelin receptor antagonist bosentan reversed the pathology fully, on the mechanistic rationale that VIP downregulates endothelin receptor expression.

Delivery is where the programme keeps stalling. Leuchte and colleagues (2008) inhaled a single 100 microgram aerosol in 20 patients during right heart catheterisation and measured a modest, selective and temporary pulmonary vasodilation with improved stroke volume and mixed venous oxygen saturation, no systemic blood pressure effect and no adverse events, with six of 20 dropping pulmonary vascular resistance more than 20%. The same group showed in 2015 in the isolated rabbit lung, under a threefold pressure rise induced by the thromboxane mimetic U46619, that thiorphan does nothing on its own but significantly augments and prolongs the effect of inhaled VIP, which identifies neutral endopeptidase 24.11 on the lung surface as the enzyme limiting the response.

Aviptadil is synthetic human VIP developed as a drug substance under the trade name ZYESAMI and the development code RLF-100. The rationale for testing it in COVID-19 respiratory failure came from VIP's concentration in alveolar type II cells and its cytoprotective effects there. That rationale was reasonable. The trial results did not support it, and the record is frequently misdescribed.

The definitive study is TESICO, the ACTIV-3b platform trial run by NIAID across 28 United States sites and published by Brown and colleagues in Lancet Respiratory Medicine in 2023. It enrolled 473 participants between April 2021 and May 2022 in a two-by-two factorial design; 471 were randomly assigned to intravenous aviptadil or matched placebo, with 461 in the modified intention-to-treat population. Aviptadil was given as a 12-hour infusion on each of three consecutive days at 600, 1200 and 1800 pmol/kg. The primary endpoint was a six-category ordinal outcome at day 90. The odds ratio for being in a better category was 1.11 (95% CI 0.80 to 1.55, p=0.54), and mortality by day 90 was 38% with aviptadil against 36% with placebo (hazard ratio 1.04, 95% CI 0.77 to 1.41, p=0.78). The trial concluded that aviptadil did not significantly improve clinical outcomes up to day 90.

The inhaled programme did not reach a positive read either. The Phase 2/3 inhaled ZYESAMI study (NCT04360096) was terminated after 144 participants, a second inhaled Phase 3 (NCT05137795) was withdrawn before enrolling anyone, and an investigator-led inhaled Phase 2 in Switzerland (NCT04536350) was terminated at 83 participants. A 2025 systematic review and meta-analysis of the randomised evidence found no significant survival benefit, with an odds ratio of 1.01 (95% CI 0.72 to 1.42, p=0.93), while noting that uncontrolled case series had reported oxygenation and inflammatory marker improvements.

Aviptadil holds no marketing authorisation in the United States, Canada, the United Kingdom, the European Union or Australia for any respiratory indication. An emergency use authorisation was sought for COVID-19 and was not granted. It does hold United States orphan drug designation for pulmonary arterial hypertension, which is a designation covering rare-disease development incentives and is not a finding of efficacy. Aviptadil is also a component of a combination product with phentolamine marketed in some European countries under the name Invicorp for an unrelated indication; that authorisation says nothing about the respiratory work.

The immunology is the second-strongest arm of the VIP literature after the circadian work. VIP is released by neurons and by immune cells themselves, and VPAC1 is constitutively expressed on resting T cells and macrophages while VPAC2 is induced on activation, which gives the system a built-in state dependence. Delgado and Ganea's 2013 review in Amino Acids is the standard synthesis.

The pattern is consistent across models. In collagen-induced arthritis, Delgado and colleagues (2001) reported abrogated joint swelling and preserved cartilage and bone, with both the inflammatory and the autoimmune components of the model suppressed. In myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, Gonzalez-Rey and colleagues (2006) found reduced incidence and severity with suppressed central nervous system inflammation and blocked encephalitogenic T cell reactivity, effective when started after disease was established rather than only prophylactically. Fernandez-Martin and colleagues (2006) identified the cellular mechanism in the same model: VIP expanded CD4+CD25+Foxp3+ regulatory T cells in the periphery and the nervous system, those cells were more suppressive on a per-cell basis than controls, and adoptive transfer moved the suppression to naive recipients.

The sarcoidosis study is what makes this more than a rodent story. Prasse and colleagues (American Journal of Respiratory and Critical Care Medicine, 2010) treated 20 patients with histologically proven active sarcoidosis with nebulised VIP for four weeks in an open Phase 2 design. TNF-alpha production by bronchoalveolar lavage cells fell significantly, and CD4+CD127-CD25+ lavage T cells rose in number and demonstrated regulatory activity against conventional effector T cells. Paired in vitro experiments converted naive CD4+CD25- cells into CD4+CD25+Foxp3+ cells. This is the first direct demonstration of a VIP immunoregulatory effect in humans, and it uses the airway to sidestep the plasma clearance problem rather than solving it.

Receptor-selective agonists are the current direction of travel. Mosley and colleagues (2019) reported that the VPAC2-selective agonist LBT-3627 raised regulatory T cell activity without changing regulatory T cell numbers in both 6-hydroxydopamine and alpha-synuclein mouse models of Parkinson's disease, reducing inflammatory microglia and improving dopaminergic neuron survival and striatal terminal density in a concentration-dependent way. Selecting for VPAC2 is an attempt to keep the immune effect while leaving the VPAC1-mediated gut secretory and vasodilator effects behind.

VIPomas are rare neuroendocrine tumours that secrete VIP without regulation, accounting for roughly 2% of pancreatic neuroendocrine tumours. The resulting Verner-Morrison syndrome, watery diarrhoea with hypokalaemia and achlorhydria, is a direct readout of VIP pharmacology at the intestinal epithelium: sustained VPAC1 occupancy drives cAMP-dependent chloride and water secretion faster than the colon can reabsorb it. As a natural experiment in chronic exposure, it is more informative than most infusion studies, because it shows which effects persist rather than tachyphylax.

A recent multicentre series of 70 VIPoma patients reported by Bartsch and colleagues found serum VIP more than twice the upper limit of normal in 52 of them (88%), a median Ki-67 index of 5% with a range from 1% to 40%, and median overall survival of 142 months in stage IV disease. The tumours are indolent relative to most pancreatic malignancy, and the morbidity is largely secretory rather than oncological.

The diagnostic threshold is worth knowing because it is widely quoted wrongly. Korleski and colleagues examined the commonly cited 75 pg/mL plasma VIP cut-off and found a positive predictive value for VIPoma of only 12%, with 442 pg/mL performing far better as a discriminating threshold (odds ratio 11.96, p=0.01). A modestly raised plasma VIP is a common incidental finding and a poor stand-alone signal.

Native VIP terminates in Asn28 as a C-terminal alpha-amide, installed on the precursor by the peptidylglycine alpha-amidating monooxygenase system, which Yonekura and colleagues (2023) describe as a two-step reaction catalysed by two enzymes encoded in a single transcript, the monooxygenase and the amidoglycolate lyase. The amide is a receptor recognition element in the secretin/glucagon family, not a synthetic convenience, and the free-acid analogue is a distinct chemical entity with different receptor behaviour.

Amidation changes the mass by slightly under one dalton, because a terminal hydroxyl is replaced by an amino group. The amidated peptide is C147H238N44O42S at 3,325.8 g/mol; the free acid is C147H237N43O43S at 3,326.8 g/mol. Both numbers are in circulation and they are routinely paired with the wrong formula. PubChem's entries for VIP (CID 53314964) and for aviptadil (CID 16132300) both display the free-acid formula and 3,326.8 g/mol, and that is where the higher figure in most catalogue records, including this one, originates. If a specification sheet quotes 3,325.8 g/mol next to C147H237N43O43S, or 3,326.8 next to C147H238N44O42S, the two lines disagree with each other and at least one is copied.

Registry numbers carry a parallel confusion. 37221-79-7 is the registry number for vasoactive intestinal peptide itself, linked to UNII 6J2WVD66KR and KEGG C16119. 40077-57-4 is registered to aviptadil, UNII A67JUW790C, the same 28-residue sequence carried as a named drug substance. They are not two different molecules and they are not interchangeable identifiers, and mass spectrometry cannot tell them apart. A third number occasionally appearing on product listings, 37239-35-5, does not correspond to this peptide.

Met17 is the only sulfur-containing residue in the sequence and it is the practical stability liability. Methionine sulfoxide formation is the first degradation product to appear on stability HPLC, it adds 16 daltons, and it is not visible on a purity figure quoted without a chromatogram. Oxidation is accelerated by dissolved oxygen, by trace transition metals and by vigorous agitation, which is why aggressive vortexing of a reconstituted vial is a worse idea for this peptide than for most. The two aspartate residues at positions 3 and 8, each followed by an asparagine or a tyrosine, are the secondary concern, since Asp-Asn and Asn-Tyr motifs support deamidation and isoaspartate formation over longer solution storage.

Analytical characterisation that actually settles identity for a 28-mer needs three things together: reversed-phase HPLC purity with the chromatogram attached rather than a single percentage, high-resolution mass spectrometry with the observed monoisotopic mass compared against the amide rather than the acid, and amino acid analysis or sequencing to distinguish VIP from the co-encoded PHM-27, which shares the same precursor, a similar length at 27 residues, the same secretin-family N-terminal architecture and a close molecular weight.

PACAP is the closest relative and the comparison most often asked for. PACAP-27 shares roughly two thirds of its residues with VIP, and the two peptides bind VPAC1 and VPAC2 with broadly comparable affinity, which is why receptor-level attribution in this family needs genetics or selective ligands. What separates them is PAC1, a receptor PACAP prefers by more than a hundredfold and VIP does not meaningfully engage. PACAP was identified in 1989 from ovine hypothalamus, nineteen years after VIP, and its distinctive pharmacology, including the trigeminovascular effects relevant to migraine, is largely PAC1 territory. Cross-reading a PACAP result onto VIP is safe only where the effect is VPAC-mediated.

Secretin and glucagon sit further out in the same superfamily, sharing the N-terminal architecture that class B receptors read but diverging enough in the C-terminal half that receptor selectivity is clean. GHRH is the family member with the most distinct downstream biology despite the shared fold. PHM-27 is the odd case: it comes from the same precursor as VIP, and it has been reported to act as an agonist at the calcitonin receptor with efficacy comparable to calcitonin, which is a target outside the family entirely.

Within this catalogue, VIP overlaps functionally with the other immune-directed entries but not mechanistically. KPV, the C-terminal tripeptide of alpha-MSH, suppresses NF-kappaB through melanocortin-independent intracellular action and has no GPCR of its own in that role. Thymosin alpha-1 works on Toll-like receptor signalling and dendritic cell maturation rather than through a Gs-coupled receptor. All three converge on reduced NF-kappaB-driven cytokine transcription from different directions, and only VIP carries a demonstrated regulatory T cell induction result in humans.