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. 2013 Dec 30;2013(4):343-7.
doi: 10.5339/gcsp.2013.39. eCollection 2013.

The discovery of PCSK9 inhibitors: A tale of creativity and multifaceted translational research

Ahmed Elguindy  1 , Magdi H Yacoub  2
Affiliations

The discovery of PCSK9 inhibitors: A tale of creativity and multifaceted translational research

Ahmed Elguindy et al. Glob Cardiol Sci Pract. .
No abstract available

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Figures

Figure 1.
Figure 1.
LDL receptor pathway of mammalian cells (from Goldstein J and Brown S. The LDL Receptor. Arterioscler Thromb Vasc Biol. 2009;29:431–438).
Figure 2.
Figure 2.
Joseph L. Goldstein and Michael S. Brown.
Figure 3.
Figure 3.
Nabil Seidah.
Figure 4.
Figure 4.
Subcellular localization of proprotein convertases. Upon exiting the endoplasmic reticulum (ER), most of the basic amino acid-specific proprotein convertases traverse the Golgi apparatus towards the trans-Golgi network (TGN). The activated membrane-bound subtilisin kexin isozyme 1 (SKI1) is mostly concentrated in the cis- and medial-Golgi, from where it is then sent to lysosomes for degradation, and does not normally reach the cell surface. Proprotein convertase subtilisin kexin 9 (PCSK9) is secreted from the TGN directly into the medium as an enzymatically inactive non-covalent complex of the protease and its prosegment. Upon binding to the low-density lipoprotein receptor (LDLR) at the cell surface, the PCSK9–LDLR complex is internalized into endosomes and then sent to lysosomes for degradation. (from Seidah N and Prat A. The biology and therapeutic targeting of proprotein convertases. Nat Rev Drug Discov. 2012 May;11(5):367–83).
Figure 5.
Figure 5.
A: Model of PCSK9-mediated sorting of LDL receptors to lysosomes. The EGFa domain of the LDL receptor is required for proper sorting of the LDL receptor back to the cell surface. The EGFa domain may contain a sorting signal that interacts with an endosomal protein (green star), directing the LDL receptor back to the cell surface on recycling endosomes (green arrows). Binding of PCSK9 might interfere with that signal, preventing the LDL receptor from returning to the cell surface. Alternatively, PCSK9 could contain a distinct sorting signal (red star) that results in the sorting of the PCSK9-LDL receptor complex (red arrows) to lysosomes. The gain-of-function mutation involving S127 of PCSK9 may enhance the sorting of the PCSK9-LDL receptor complex to lysosomes. B: The structure of the LDL receptor and PCSK9 at endosomal pH. The LDL receptor is folded back upon itself at low pH; however, the face of the EGFa domain that binds PCSK9 is exposed. The LDL receptor-binding site on PCSK9 is at the apex of a roughly triangular structure formed by the tripartite domain structure of PCSK9. The D374 residue that is altered in gain-of-function PCSK mutants is located within the apical LDL receptor-binding site, whereas the S127 residue is quite distant from the binding interface. S127 mutations do not affect binding of PCSK9 to the LDL receptor. Gain-of-function mutations affecting residue 127 may reduce LDL receptors by enhancing the sorting of LDL receptors to lysosomes, rather than by affecting the strength of PCSK9-LDL receptor interactions. (figure and accompanying legend from Peterson A, Fong L and Young S. PCSK9 function and Physiology. J Lipid Res. 2008 June; 49(6): 1152–1156).
Figure 6.
Figure 6.
Total cholesterol, LDL-C and HDL-C levels after injection of a neutralizing monoclonal antibody against PCSK9 compared to a control antibody against keyhole limpet hemocyanin (KLH). Results are expressed as mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001 vs. anti-KLH control antibody at the same time point, n = 4 per group. (from Chan J. et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9820–5).
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