The connecting peptide (C‐peptide) has received increased attention for its potential therapeutic effects in ameliorating illnesses such as kidney disease and diabetes. Although the mechanism of C‐peptide signaling remains elusive, evidence supports its internalization and intracellular function. Emerging research is uncovering the diverse biological roles metals play in controlling and affecting the function of bioactive peptides. The work presented herein investigates interactions between C‐peptide and first‐row d‐block transition metals, as well as their effects on C‐peptide internalization into cells. Through spectroscopic techniques, it is demonstrated that CrIII, CuII, and ZnII bind to C‐peptide with differing stoichiometries and biologically relevant affinities. In addition, metal binding elicits both subtle changes in secondary structure and inhibits adoption of an α‐helical character in environments where the dielectric constants are reduced. This study shows how metal ions can modulate peptide hormone activity through subtle structural changes to disrupt cellular uptake.

The proinsulin connecting peptide, C‐peptide, is released in equimolar amounts and might be an active hormone. The exact function of C‐peptide remains unclear, but its activity might depend on metal ions. As depicted in this cover art, bioavailable metals could be the missing piece to elucidate C‐peptide′s activity. More information can be found in the communication by M. C. Heffern et al. on page 2447 in Issue 19, 2019 (DOI: 10.1002/cbic.201900172).