Peptide drugs face low bioavailability when taken orally due to rapid degradation by digestive enzymes and poor absorption through the gut lining. However, systemic absorption is not required to treat gastrointestinal diseases if the therapeutic effect can be achieved locally in the gastrointestinal tract. The gut lumen contains receptors that can be targeted for orally administered peptide drugs. Disulfide-rich peptide scaffolds derived from venomous animals and plant toxins offer a structurally diverse and biologically intriguing class of compounds with strong therapeutic potential. Their inherent stability makes them promising candidates for development into orally bioavailable drugs. Venomous species such as snakes, spiders, and cone snails produce disulfide-rich peptides with diverse structural motifs, including inhibitor cysteine knot of cone snails, cysteine-stabilised peptides of scorpions, boundless b‑hairpins of sea anemones, and three-finger toxins of snakes. These scaffolds play critical roles in displaying pharmacophores for predator-prey interactions and have evolved to modulate various physiological targets with remarkable specificity. Their diverse architectures enable precise modulation of cellular pathways, making them attractive leads for therapeutic intervention in diseases ranging from cancer to neurological conditions. Disulfide bonds contribute to structural stability and the ability to resist enzymatic degradation, which is of interest to us for developing oral peptide drug strategies. Understanding these peptide’s structural diversity and evolutionary adaptations is significantly important for harnessing their full therapeutic potential in biomedical research and drug development.
By leveraging advanced mass spectrometric and de novo sequencing techniques, we aim to identify disulfide-rich peptide scaffolds that can retain their activity and stability under gastrointestinal conditions. At the same time, it addresses a gap in the systematic analysis of the disulfide-rich scaffolds from nature, including venomous organisms and plants, and it provides a new methodology for carrying out such a study. This systematic study will assess the stability of representative disulfide-rich folds and scaffolds across various parameters, including serum, temperature, pH, and proteolytic enzymes.