Abstract
Venoms act with remarkable specificity upon a broad diversity of physiological targets. Venoms are composed of proteins, peptides, and small molecules, providing the foundation for the development of novel therapeutics. This study assessed the effect of venom from the red-bellied black snake (Pseudechis porphyriacus) on human primary leukocytes using bead-based flow cytometry, mixed lymphocyte reaction, and cell viability assays. We show that venom treatment had a significant immunosuppressive effect, inhibiting the secretion of interleukin (IL)-2 and tumor necrosis factor (TNF) from purified human T cells by 90% or greater following stimulation with mitogen (phorbol 12-myristate 13-acetate and ionomycin) or via cluster of differentiation (CD) receptors, CD3/CD28. In contrast, venom treatment did not inhibit TNF or IL-6 release from antigen-presenting cells stimulated with lipopolysaccharide. The reduced cytokine release from T cells was not associated with inhibition of T cell proliferation or reduction of cell viability, consistent with an anti-inflammatory mechanism unrelated to the cell cycle. Deconvolution of the venom using reverse-phase HPLC identified four fractions responsible for the observed immunosuppressive activity. These data suggest that compounds from P. porphyriacus venom may be potential drug leads for T cell-associated conditions such as graft versus host disease, rheumatoid arthritis, and inflammatory bowel disease.
Highlights
Captopril, the first commercially licensed venom-derived drug, was developed in 1981 from a peptide found in venom of the pit viper Bothrops jararaca [1]
An initial venom screen showed that following 24 h of treatment, RBB venom (RBBV) suppressed the secretion of proinflammatory tumor necrosis factor (TNF), but not IL-6, from peripheral blood mononuclear cells (PBMCs) stimulated with the mitogen phorbol 12-myristate 13-acetate and ionomycin (P/I), but not LPS (Figure A1)
Treatment with RBBV completely inhibited mitogen-induced IL-2 and TNF secretion and caused a 90% reduction in cytokine secretion following T cell receptor (TCR) activation (Figure 1a–d), which was equivalent to the suppression achieved with CsA
Summary
The first commercially licensed venom-derived drug, was developed in 1981 from a peptide found in venom of the pit viper Bothrops jararaca [1]. Five other venom-derived drugs, from snakes, leech, cone snail, and lizard, have subsequently received U.S Food and Drug. While recent reviews have highlighted some common challenges associated with venom-drug discovery [5,6], several promising leads appear to work via immune-mediated mechanisms [7,8]. Venom from the South American rattlesnake Crotalus durissus terrificus and the Chinese cobra Naja naja atra have received considerable attention for their immune-modulating activity, whereas venoms from Australian snakes have not been investigated. C. durissus terrificus causes significant mortality across South America, yet components of its venom have been extensively researched for potential therapeutic applications [9,10,11,12]. In vitro studies have shown that the venom’s principal neurotoxin, crotoxin (CTX), and its isolated basic phospholipase A2
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