Structure and biological activity of a conformational constrained apolipoprotein A-I-derived helical peptide targeting the protein haptoglobin

Novel pharmacological treatments for atherosclerosis is an active research field in medicinal chemistry. It was shown that the acute phase protein haptoglobin (Hpt) plays a role in modulating the reverse cholesterol transport binding to the HDL-major protein Apolipoprotein A-I and impairing the activity of the Lecithin-Cholesterol AcylTransferase (LCAT). We reported that the peptide P2a restores the LCAT activity in presence of Hpt in vitro and in vivo. Now, we design and characterize a constrained P2a analogue, ApoAib, with the intent of improving Hpt binding and the metabolic stability. ApoAib is a well folded α-helical peptide with high proteolytic stability in serum. It binds to Hpt, impairs haptoglobin binding to HDL, and restores LCAT activity in presence of haptoglobin. Furthermore, an interaction analysis using NMR revealed the peptide binding site involved in haptoglobin molecular recognition. Therefore, ApoAib represents a promising candidate to improve reverse cholesterol transport for application in cardiovascular diseases.