VIP

Vasoactive Intestinal Peptide (VIP) is a 28-amino acid endogenous neuropeptide found throughout the central and peripheral nervous systems and gut. Its synthetic pharmaceutical form, aviptadil, has been investigated for COVID-19 respiratory failure, MCAS, and autoimmune conditions. VIP suppresses inflammatory cytokine cascades and modulates mast cell behavior, making it a candidate for chronic inflammatory and post-viral syndromes including long COVID.

VIP binds to VPAC1 and VPAC2 receptors (G-protein coupled receptors), activating adenylate cyclase and elevating intracellular cAMP. This signaling cascade suppresses the release of pro-inflammatory cytokines including TNF-α, IL-6, and IL-12, while promoting regulatory T-cell differentiation. In the lung, VIP binds AT2 cell VPAC1 receptors, upregulating surfactant production, blocking apoptosis, and inhibiting cytokine-mediated lung injury. It also mediates shedding of ACE2 and TMPRSS2 surface expression via ADAM10 sheddase upregulation, reducing viral entry points. In mast cells, while VIP can trigger degranulation in isolation, within neuroimmune contexts it reprograms mast cells toward a non-degranulating phenotype, offering paradoxical anti-inflammatory protection relevant to MCAS.

Aviptadil received FDA Fast Track designation for critical COVID-19 with respiratory failure. Phase 2 trials showed improved 60-day survival in some cohorts, though a Lancet Respiratory Medicine Phase 3 trial found no significant difference in the primary endpoint. Observational studies report elevated endogenous VIP plasma correlates with COVID-19 survival. Preclinical and clinical case data support a role in MCAS and long COVID neuroinflammation, though no large RCTs exist for these indications. Research into autoimmune applications (IBD, rheumatoid arthritis) continues in preclinical models.

Peptides commonly paired with VIP for synergistic effects.