12:00 AM
Feb 06, 2014
 |  BC Innovations  |  Targets & Mechanisms

PCSK9 peptide inhibitors

Although at least 10 companies are chasing inhibitors of PCSK9 for decreasing low-density lipoprotein cholesterol, the compounds dominating the field are antibodies or siRNAs that require injection. Roche'sGenentech Inc. unit and a separate team from Pfizer Inc. and The University of Queensland are betting that peptides might provide an oral competitor and have identified short peptide fragments that inhibit binding of PCSK9 to its target.1,2 Optimizing the potency and stability for oral delivery is the next challenge.

Genentech is not disclosing plans for future development of the peptides. Pfizer did not reply to enquiries regarding future plans for its compounds.

The low-density lipoprotein receptor (LDLR) decreases circulating LDL cholesterol by binding the lipid at the hepatocyte cell surface, causing internalization of the LDL-LDLR complex. Inside the cells, LDLR dissociates from LDL and recycles to the cell surface, whereas the lipid is degraded by the lysosome.

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a key regulator of LDL that acts by decreasing surface levels of LDLR, which reduces uptake of the lipid from the blood.

PCSK9 is synthesized as an inactive proenzyme and undergoes autocatalysis to form the active protein that binds LDLR. When the PCSK9-bound LDLR binds LDL, the whole complex is internalized. PCSK9 then directs the bound LDLR to the lysosome, where it is degraded and prevented from recycling to the cell surface (see "PCSK9-mediated regulation of LDLR levels").

The protein has thus become the focus of intense activity as a target for lowering circulating LDL by blocking the interaction between PCSK9 and LDLR.

Several PCSK9-targeted antibodies and siRNA candidates are in clinical and preclinical development for various dyslipidemias (see Figure 1, "PCSK9-mediated regulation of LDLR levels"). However, these compounds all require parenteral administration, and orally available inhibitors still...

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