Potent Lys Patch-Containing Stapled Peptides Targeting PCSK9

Proprotein
convertase subtilisin/kexin type 9 (PCSK9), identified
as a regulator of low-density lipoprotein receptor (LDLR), plays a
major role in cardiovascular diseases (CVD). Recently, Pep2-8, a small
peptide with discrete three-dimensional structure, was found to inhibit
the PCSK9/LDLR interaction. In this paper, we describe the modification
of this peptide using stapled peptide and SIP technologies. Their
combination yielded potent compounds such as 18 that
potently inhibited the binding of PCSK9 to LDLR (KD = 6 ± 1 nM) and restored in vitro LDL uptake by
HepG2 cells in the presence of PCSK9 (EC50 = 175 ±
40 nM). The three-dimensional structures of key peptides were extensively
studied by circular dichroism and nuclear magnetic resonance, and
molecular dynamics simulations allowed us to compare their binding
mode to tentatively rationalize structure–activity relationships
(SAR).