Potent Lys Patch-containing Stapled Peptides Targeting PCSK9

Kévin Bourbiaux (1) , Baptiste Legrand (1) , Pascal Verdié (1) , Sergio Mallart (2) , Géraldine Manette (2) , Claire Minoletti (2) , J. David David Stepp (3) , Philippe Prigent (2) , Jean-Christophe Le Bail (2) , Laurence Gauzy-Lazo (2) , Olivier Duclos (2) , Jean Martinez (1) , Muriel Amblard (1)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 Sanofi Aventis R&D [Chilly-Mazarin]
3 Sanofi US

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 by 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).

Mots clés: PCSK9; Pep2-8; SIP technology; Stapled peptides; LDL uptake. 2

Domaines: Chimie thérapeutique; Biologie structurale [q-bio.BM]

Kévin Bourbiaux, Baptiste Legrand, Pascal Verdié, Sergio Mallart, Géraldine Manette, et al.. Potent Lys Patch-containing Stapled Peptides Targeting PCSK9. Journal of Medicinal Chemistry, 2021, 64 (15), pp.10834-10848. ⟨10.1021/acs.jmedchem.0c02051⟩. ⟨hal-03371411⟩