Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design.
Candice AlleyneRupesh P AminBhavana BhattElisabetta BianchiJ Craig BlainNicolas BoyerDanila BrancaMark W EmbreySookhee N HaKelli JetteDouglas G JohnsAngela D KerekesKenneth A KoeplingerDerek LaPlacaNianyu LiBeth MurphyPeter OrthAlonso RicardoScott SaloweKathleen SeybAurash ShahripourJoseph R StringerYili SunRodger TracyChengwei WuYusheng XiongHyewon YoumHratch J ZokianThomas J TuckerPublished in: Journal of medicinal chemistry (2020)
Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. In this paper, we describe a series of novel cyclic peptides derived from an mRNA display screen which inhibit the protein-protein interaction between PCSK9 and LDLR. Using a structure-based drug design approach, we were able to modify our original screening lead 2 to optimize the potency and metabolic stability and minimize the molecular weight to provide novel bicyclic next-generation PCSK9 inhibitor peptides such as 78. These next-generation peptides serve as a critical foundation for continued exploration of potential oral, once-a-day PCSK9 therapeutics for the treatment of cardiovascular disease.
Keyphrases
- low density lipoprotein
- cardiovascular disease
- coronary artery disease
- protein protein
- high throughput
- amino acid
- type diabetes
- heart failure
- metabolic syndrome
- emergency department
- transcription factor
- coronary artery bypass grafting
- smoking cessation
- replacement therapy
- aortic valve
- adverse drug
- left ventricular
- ejection fraction
- cardiovascular risk factors