The emerging landscape of peptide-based inhibitors of PCSK9

• Published in: Atherosclerosis 2021-08, Vol.330, p.52-60
• Main Authors: Tombling, Benjamin J., Zhang, Yuhui, Huang, Yen-Hua, Craik, David J., Wang, Conan K.
• Format: Article
• Language: English
• Subjects: Combinatorial libraries; Disulfide-rich peptides; PCSK9; Peptides; Protein-protein interaction
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2021.06.903

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a clinically validated target for treating cardiovascular disease (CVD) due to its involvement in cholesterol metabolism. Although approved monoclonal antibodies (alirocumab and evolocumab) that inhibit PCSK9 function are very effective in lowering cholesterol, their limitations, including high treatment costs, have so far prohibited widespread use. Accordingly, there is great interest in alternative drug modalities to antibodies. Like antibodies, peptides are valuable therapeutics due to their high target potency and specificity. Furthermore, being smaller than antibodies means they have access to more drug administration options, are less likely to induce adverse immunogenic responses, and are better suited to affordable production. This review surveys the current peptide-based landscape aimed towards PCSK9 inhibition, covering pre-clinical to patented drug candidates and comparing them to current cholesterol lowering therapeutics. Classes of peptides reported to be inhibitors include nature-inspired disulfide-rich peptides, combinatorially derived cyclic peptides, and peptidomimetics. Their functional activities have been validated in biophysical and cellular assays, and in some cases pre-clinical mouse models. Recent efforts report peptides with potent sub-nanomolar binding affinities to PCSK9, which highlights their potential to achieve antibody-like potency. Studies are beginning to address pharmacokinetic properties of PCSK9-targeting peptides in more detail. We conclude by highlighting opportunities to investigate their biological effects in pre-clinical models of cardiovascular disease. The anticipation concerning the PCSK9-targeting peptide landscape is accelerating and it seems likely that a peptide-based therapeutic for treating PCSK9-mediated hypercholesterolemia may be clinically available in the near future. [Display omitted] •Many peptides have been discovered to inhibit PCSK9, demonstrating wide interest in peptide-based PCSK9 antagonistic drugs.•The ability of peptides to inhibit PCSK9 and restore cholesterol metabolism validate their therapeutic potential.•Peptides have in vitro activities comparable to that of monoclonal antibodies, showing they are viable as drugs.•Peptides are amenable to chemical optimization to improve drug-like properties.•The clinical efficacy of peptides, particularly for the direct treatment of atherosclerosis, has been underexplored.