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.
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. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely
potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules
such as 44 demonstrated sufficient oral bioavailability
to maintain therapeutic levels in rats and cynomolgus monkeys after
dosing with an enabled formulation. We demonstrated target engagement
and LDL lowering in cynomolgus monkeys essentially identical to those
observed with the clinically approved, parenterally dosed antibodies.
These molecules represent the first report of highly potent and orally
bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles
favorable for potential development as once-daily oral lipid-lowering
agents. In this manuscript, we detail the design criteria and multiparameter
optimization of this novel series of PCSK9 inhibitors.
Highlights d Unprecedented allosteric small-molecule binder to PCSK9 was identified using AS/MS d Biased and unbiased hit-to-lead strategy identified binders through divergent SAR d Demonstrated binding of lead compound to PCSK9 in a cellular thermal shift assay d Developed lead compound into targeted degrader achieving 60% reduction of PCSK9 levels
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