Intercellular communication poses a fundamental challenge for multicellular organisms, leading to the evolution of peptidergic signaling as a main mechanism to facilitate communication. In animals, peptidergic signaling predominantly operates through G protein-coupled receptors (GPCRs), though other receptor types also exist. These intricate signaling systems are vulnerable to exploitation by exochemicals. We have previously shown that doppelganger toxins - peptides that hijack the prey’s endogenous signaling system through mimicking prey hormones and neuropeptides hold promise as drug candidates for various diseases. However, to fully harness the therapeutic potential of doppelganger toxins, it is essential to understand the molecular evolution of these unusual molecules. Here, I discuss four key points related to doppelganger toxin evolution and application.
First, I examine the evolutionary origins of doppelganger toxins, highlighting that while many toxins are recruited from endogenous peptides in the venomous animal, de novo origins also exist, suggesting a complex evolutionary landscape for these toxins. Second, we explore the evolutionary origins of signaling peptides, emphasizing their emergence at multiple points during metazoan evolution, and the implications for doppelganger toxin discovery. Third, we investigate the convergent evolution of doppelganger toxins, revealing that toxins often converge towards specific signaling systems. Finally, we emphasize the significance of considering the biology of the venomous organisms, for the discovery and therapeutic applications of doppelganger toxins.
Drawing upon examples from venomous marine mollusks, arthropods, reptiles, and others, we illustrate these key points and provide insights into the intricate interplay between peptidergic signaling, doppelganger toxins, and their applications in drug development.