Potential use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and prevention method in viral infection

Abstract

Cellular lipid membranes serve as the primary barrier preventing viral infection of the host cell and provide viruses with a critical initial point of contact. Occasionally, viruses can utilize lipids as viral receptors. Viruses depend significantly on lipid rafts for infection at virtually every stage of their life cycle. The pivotal role that proprotein convertase subtilisin/kexin Type 9 (PCSK9) plays in cholesterol homeostasis and atherosclerosis, primarily by post-transcriptionally regulating hepatic low-density lipoprotein receptor (LDLR) and promoting its lysosomal degradation, has garnered increasing interest. Conversely, using therapeutic, fully humanized antibodies to block PCSK9 leads to a significant reduction in high LDL cholesterol (LDL-C) levels. The Food and Drug Administration (FDA) has approved PCSK9 inhibitors, including inclisiran (Leqvio®), alirocumab (Praluent), and evolocumab (Repatha). At present, active immunization strategies targeting PCSK9 present a compelling substitute for passive immunization through the administration of antibodies. In addition to the current inquiry into the potential therapeutic application of PCSK9 inhibition in human immunodeficiency virus (HIV)-infected patients for hyperlipidemia associated with HIV and antiretroviral therapy (ART), preclinical research suggests that PCSK9 may also play a role in inhibiting hepatitis C virus (HCV) replication. Furthermore, PCSK9 inhibition has been suggested to protect against dengue virus (DENV) potentially and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses. Recent evidence regarding the impact of PCSK9 on a variety of viral infections, including HCV, HIV, DENV, and SARS-CoV-2, is examined in this article. As a result, PCSK9 inhibitors and vaccines may serve as viable host therapies for viral infections, as our research indicates that PCSK9 is significantly involved in the pathogenesis of viral infections.

Keywords: Cholesterol; Lipid; Proprotein convertase subtilisin/kexin type 9 (PCSK9); Treatment; Vaccines; Viral infection.

Fig. 1

There is a signal peptide (amino acids 1 to 30), a prodomain (amino acids 31 to 152), a catalytic domain (amino acids 153 to 452), and a C-terminal domain (amino acids 453 to 692) that make up the mature form of PCSK9. The signal peptide breaks apart when it gets to the endoplasmic reticulum (ER), and the PCSK9 zymogen is automatically made between Gln152 and Ser153 (serine-isoleucine-proline (SIP)/valine-phenylalanine-alanine-glutamine (VFAQ)152). Furin enzymes turn off the adult version of PCSK9, which is about 60 kDa long (aa 153 to 692). This makes it shorter, to 55 kDa. The orange boxed area shows the signal peptide (SP), the yellow boxed area shows the prodomain, the green boxed area shows the catalytic domain, and the blue boxed area shows the C-terminal domain [22]

Fig. 2

How lipoproteins are broken down in reaction to treatments that target PCSK9. Antisense oligonucleotides (ASOs) attach to the PCSK9 mRNA and stop it from being made. 2. Small interfering RNAs (siRNAs) stop the production of PCSK9 by encouraging the breakdown of PCSK9 mRNA. 3. Small molecule inhibitors stop PCSK9 from activating and being released from the ER, which is an essential step in the maturation process. 4. LDLR can’t connect with PCSK9 because of small peptides that look like the structure of PCSK9’s catalytic domain, C-terminal domain, or epidermal growth factor precursor homology domain-A. 5. Bancovirus monoclonal antibodies stop PCSK9 from attaching to LDLRs. Therapies that target PCSK9 improve the clearance of LDL particles through receptors by stopping LDLRs from breaking down. This encourages LDLR to return to the cell surface. Proteins that are special to PCSK9 and create higher-than-normal amounts of LDLRs may help explain why treatment causes lower levels of lipoprotein(a) (Lp(a)). A recent study backs up this theory [23, 24]

Fig. 3

Potential mechanisms contributing to increased cholesterol availability for cancer cells. PCSK9 is closely associated with the incidence and progression of several cancers. In several studies, PCSK9 siRNA was shown to effectively suppress the proliferation and invasion of several studied tumor cells. Cancer cell’s demand for cholesterol is supplied by both uptake from the blood or de novo synthesis. Therefore, high plasma cholesterol may provide such a high cancer cell requirement. On the other hand, oxidized cholesterol derivatives, namely oxysterols, show a significant apoptotic effect, thus opposing cancer cell proliferation [45]

Fig. 4

The PCSK9 effect on HCV. Numerous host factors, including heparan sulfate proteoglycans (HSPGs), low-density lipoprotein receptor (LDLR), tetraspanin CD81, claudin-1 (CLDN1), occludin (OCLN), tight junction proteins, receptor tyrosine kinases (RTKs), and the Niemann–Pick C1-like 1 (NPC1L1), are implicated in HCV entry into human hepatocytes. Activation of fatty acid and cholesterol synthesis throughout the HCV life cycle. Throughout its replicative life cycle, HCV fosters a lipid-rich environment by stimulating the expression of transcription factors that are involved in the production of cholesterol and fatty acids. Additionally, HCV increases LDLR expression on the surface of hepatocytes to facilitate entry. Microsomal triglyceride transfer protein (MTP) downregulation further inhibits the excretion of VLDL by HCV [33, 49]

Fig. 5

Through a mechanism that requires only the prodomain/catalytic subunit of mature PCSK9 to bind ACE2, extracellular PCSK9 promotes the degradation of ACE2. This mechanism likely reduces ACE2 levels on the cell surface, inhibits cell-to-cell fusion, and potentially mitigates SARS-CoV-2 infection. This figure illustrates how extracellular PCSK9, and its gain-of-function variant D374Y in particular, substantially enhanced the degradation of ACE2. Necessary for the transportation of the PCSK9-LDLR complex to endosomes/lysosomes for degradation is the CHRD domain of PCSK9, particularly its M2 module. Surprisingly, the catalytic and/or prodomain of PCSK9 appear to be the critical domains for PCSK9 activity on ACE2, not the CHRD; this distinguishes ACE2 as a unique and novel PCSK9 target, quite distinct from the LDLR and MHC-I, which may partially explain this observation [52]