Structural determinants conferring unusual long life in human serum to rattlesnake‐derived antimicrobial peptide Ctn[15‐34]

Ctn[15‐34], a downsized version of the snake venom cathelicidin‐like peptide crotalicidin (Ctn), shows an unusually high lifespan ( t 1/2 , approximately 12 h) in human serum, which significantly adds to its promise as an antimicrobial and antitumor agent. Herein we investigate the role of Ctn[15‐34] structure on serum survival. Using a set of analogs, we show that C‐terminal amidation, as well as the specific layout of the Ctn[15‐34] sequence—a helical N‐terminal domain followed by a hydrophobic domain—is crucial for slow degradation, and any change in their arrangement results in significantly lower t 1/2 . Aside from the privileged primary structure, features such as self‐aggregation can be ruled out as causes for the long serum life. Instead, studies in other protease‐rich fluids suggest a key role for certain human serum components. Finally, we demonstrate that Ctn[15‐34] is able to induce bacterial death even after 12‐hour pre‐incubation in serum, in agreement with the proteolytic data. Altogether, the results shed light on the uncommon stability of Ctn[15‐34] in human serum and confirm its potential as an anti‐infective lead.