Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment

Abstract

The proprotein convertase subtilisin/kexin-type 9 (PCSK9) binds to low-density lipoprotein receptors (LDLR), thereby trafficking them to lysosomes upon endocytosis and enhancing intracellular degradation to prevent their recycling. As a result, the levels of circulating LDL cholesterol (LDL-C) increase, which is a prominent risk factor for developing atherosclerotic cardiovascular diseases (ASCVD). Thus, PCSK9 has become a promising therapeutic target that offers a fertile testing ground for new drug modalities to regulate plasma LDL-C levels to prevent ASCVD. In this review, we have discussed the role of PCSK9 in lipid metabolism and briefly summarized the current clinical status of modalities targeting PCSK9. In particular, a detailed overview of peptide-based PCSK9 inhibitors is presented, which emphasizes their structural features and design, therapeutic effects on patients, and preclinical cardiovascular disease (CVD) models, along with PCSK9 modulation mechanisms. As a promising alternative to monoclonal antibodies (mAbs) for managing LDL-C, anti-PCSK9 peptides are emerging as a prospective next generation therapy.

Unraveling the Puzzle of Therapeutic Peptides: A Promising Frontier in Huntington’s Disease Treatment

“…Recent progress in peptide synthesis and delivery technologies has enabled substantial advancements in drug discovery. , More than 80 peptide drugs have entered the global market, and more than 100 are under clinical investigation. , Peptide-based therapeutics and vaccines have shown promising results in treating various diseases, including cardiovascular disease, diabetes, cancer, gastrointestinal disease, and infectious diseases. − Due to the vast therapeutic potential and promising market opportunities, it is expected that therapeutic peptides will continue to attract significant investment and research efforts to yield substantial long-term outcomes. , Peptide-based drugs exhibit exceptional physiochemical properties, including their larger size, greater chiral and structural complexity, and flexible backbone, which enable them to act as potent inhibitors of protein–protein interactions (PPIs). These unique characteristics make them a promising class of drugs for therapeutic development. , This therapy is beneficial for designing PPI inhibitors because these interactions are complicated to target with small molecules.…”

Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor

“…15,16 Although either PCSK9-directed small interfering RNA or mAb therapy can reduce LDL-C in patients with hypercholesterolemia, both types of therapy are dosed by injection. Despite years of effort, 17 identification of orally available small-molecule inhibitors of the PCSK9-LDLR interaction has proved elusive. Herein we describe the invention and clinical assessment of a macrocyclic peptide (MK-0616), reporting evidence of PCSK9 inhibition, and robust plasma LDL-C reduction in human participants dosed orally with the molecule.…”

Exosomes, microvesicles, and other extracellular vesicles—a Keystone Symposia report

“…PCSK9 has become a promising therapeutic target for conditions like hypercholesterolemia, since inhibiting its activity increases LDL-R levels and reduces cholesterol. 85 Work in the Kahn lab has shown that adipose tissue is a key source of circulating miRNAs that can impact distant organs, including the liver. 86 One of the ways miRNAs can enter circulation is via exosomes.…”

“…Tamires M. Zanotto from C. Ronald Kahn and Mario Saad's lab at the State University of Campinas presented unpublished work on using exosomal miRNA to target PCSK9, an enzyme released by hepatocytes that promotes LDL receptor (LDL‐R) internalization and degradation. PCSK9 has become a promising therapeutic target for conditions like hypercholesterolemia, since inhibiting its activity increases LDL‐R levels and reduces cholesterol 85 . Work in the Kahn lab has shown that adipose tissue is a key source of circulating miRNAs that can impact distant organs, including the liver 86 .…”