New Agents to Reduce Cholesterol Levels: Implications for Nephrologists

Lucia Del Vecchio; Ivano Baragetti; Francesco Locatelli


Nephrol Dial Transplant. 2020;35(2):213-218. 

In This Article

Therapeutic Inhibition of PCSK9

The inhibition of PCSK9 can be obtained with several approaches (Table 1). Evolocumab, alirocumab and bococizumab are monoclonal antibodies selectively inhibiting PCSK9. Differing from normal antibodies, they are single-domain antibodies with two heavy chains bounded by a disulphide bridge;[34] given their structure, they are easier to obtain through recombinant technologies. Evolocumab and alirocumab are fully human, neutralizing antibodies, whereas bococizumab is a hybrid humanized one. All the three molecules bind to an epitope on PCSK9 that is adjacent to the region required for LDL-R interaction, inhibit the binding of PCSK9 to the LDL-R and attenuate the PCSK9-mediated reduction in LDL-R protein levels, thereby increasing LDL uptake.[35]

PCSK9 activity can also be inhibited by small peptides interfering with the interaction between PCSK9 and the LDL-R. A small synthetic peptide (Pep 2–8) mimics the structure of the EGF-A domain; it binds competitively to the active site of circulating PCSK9, inhibiting its action.[36] Unfortunately, its binding affinity is too weak for clinical use. Sx-PCK9 is another oral PCSK9 antagonist under preclinical development. Adnectins are a family of proteins derived from human fibronectin-10th-type III-domain and engineered for high-affinity target binding. BMS-962476 is an ~11 kDa polypeptide conjugated to polyethylene glycol that binds with subnanomolar affinity to human PCSK9. In hypercholesteraemic transgenic mice, BMS-962476 rapidly lowered cholesterol and free PCSK9 levels.[37]

Another promising strategy is the administration of small, double-strain, silencing RNAs (siRNA). These molecules interfere with the expression of the PCSK9 gene with complementary nucleotide sequences and affect the degradation of mRNA post-transcription, preventing translation.[38] Given that the promoter of the PCSK9 gene contains an SRE sequence sensitive to SREBP, the same approach can be used to inhibit the expression of SREBP and block the transcription process.[39]