Cardiovascular disease remains the leading cause of death worldwide despite the extensive pharmacological arsenal available for its treatment, underscoring the need for new therapeutic discovery strategies.1 Animal venoms contain evolutionarily optimised peptide libraries that act with remarkable potency and selectivity on druggable targets in cardiovascular physiology, including ion channels, receptors and enzymes, making them a largely underexplored source of cardiovascular modulators.2 Over the last two decades, venom-derived peptides have provided some of the clearest examples of natural products translated into modern medicines. Although relatively few have reached clinical practice, their influence on cardiovascular pharmacology has been substantial.3
We have developed an integrated discovery platform that brings together venomics, peptide chemistry and functional screening in human-induced pluripotent stem cell-derived cardiomyocytes. Snake and scorpion venoms were fractionated and fingerprinted by liquid chromatography-mass spectrometry to map their peptide composition and guide the selection of samples for functional testing. Their cardiac effects were examined through live-cell fluorescence imaging of intracellular calcium, providing real-time readouts of cardiomyocyte beating, rhythm, excitability and calcium handling. Peptides previously identified through in-house sequence-mining approaches were also chemically synthesised and evaluated in the same system.
Screening revealed distinct and reproducible response profiles across venom samples, isolated fractions and synthetic peptides. Specific snake venom fractions altered beat rate, interrupted calcium transients or produced irregular changes in transient frequency, whereas others induced sustained changes in cellular excitability. These phenotypes highlight that venom components influence cardiac activity through functionally distinct mechanisms. They also enabled active fractions to be distinguished from samples with limited or non-specific effects, providing a basis for prioritising candidates for further characterisation. In addition, sequence-mined venom peptides restored spontaneous calcium transients in cardiomyocytes that had ceased beating. This preliminary observation suggests that venom peptides may serve as useful tools for investigating the mechanisms underlying suppressed or impaired cardiac activity. Venom-induced phenotypes are now being further benchmarked against responses produced by established cardiovascular drugs to generate reference profiles that help distinguish potentially useful modulation from effects associated with toxicity or cellular stress.
This work establishes a scalable, human-relevant platform for discovering and characterising venom peptides that modulate cardiac calcium handling. Our platform links venom peptides to cardiac phenotypes and provides a basis for new molecular probes in cardiovascular peptide drug discovery.