A small molecule inhibitor of PCSK9 that antagonizes LDL receptor binding via interaction with a cryptic PCSK9 binding groove

Evison, Benny J.; Palmer, James T.; Lambert, Gilles; Treutlein, Herbert; Zeng, Jun; Nativel, Brice; Chemello, Kévin; Zhu, Qing; Wang, Jie; Teng, Yanfen; Tang, Wei; Xu, Yanfeng; Rathi, Anuj K.; Kumar, Sanjay; Suchowerska, Alexandra K.; Parmar, Jasneet; Dixon, Ian M.C.; Kelly, Graham; Bonnar, J.

doi:10.1016/j.bmc.2020.115344

Cited by 36 publications

(25 citation statements)

References 40 publications

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“…In a previous in vitro study, increased PCSK9 plasma concentrations were attributed to nilotinib‐induced impairment of PCSK9 uptake by the LDL receptor, and these inhibitory effects of nilotinib on PCSK9 binding with the LDL receptor were dependent on the concentration of nilotinib; 25 however, this result obtained from an in vitro study 25 did not completely correspond with our current clinical data. In vitro study, nilotinib was found to inhibit the interaction between PCSK9 and the LDL receptor with an average assay half‐maximal inhibitory concentration (IC 50 ) of 9.8 μmol/L (5189 ng/mL) 25 . This IC 50 of 9.8 μmol/L is quite high compared with the expected nilotinib C 0 of 900 ng/mL (1.7 μmol/L) in patients with CML 23,24 .…”

Section: Discussioncontrasting

confidence: 85%

Effects of proprotein convertase subtilisin/kexin type 9 and nilotinib plasma concentrations on nilotinib‐induced hypercholesterolaemia in patients with chronic myeloid leukaemia

et al. 2020

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What is known and objective The purpose of this study was to investigate the relationships among nilotinib plasma trough concentration (C0), low‐density lipoprotein (LDL) cholesterol, and PCSK9 plasma concentration in 31 patients with chronic myeloid leukaemia. Methods Plasma concentrations of nilotinib and PCSK9 were measured by high‐performance liquid chromatography and enzyme‐linked immunosorbent assays, respectively. Results and discussion LDL cholesterol concentrations at 1 month after nilotinib treatment were significantly increased compared with those before therapy. The mean C0 (±SD) of nilotinib at 1, 2, and 3 months after nilotinib treatment were 645 ± 516, 902 ± 623, and 951 ± 1088 ng/mL, respectively. Mean PCSK9 concentrations at 3 months after nilotinib treatment were significantly higher than those at the start of therapy (320 vs 257 ng/mL, respectively, P = .019). When the change rate in the PCSK9 concentration induced by nilotinib was classified with a cut‐off value of +40%, the change rate in LDL cholesterol in patients with a change rate in PCSK9 of ≥40% was significantly higher than that in patients with a PCSK9 change rate of <40% (67.1% vs 38.0%, P = .043); however, there were no differences in mean nilotinib C0. What is new and conclusion Nilotinib may lead to hypercholesterolaemia by increasing plasma concentrations of PCSK9 after indirect inhibition of mammalian target of rapamycin (mTOR) complex 1. In addition, certain patients seem to have high sensitivity for nilotinib in a signalling cascade of the PI3K/Akt/mTOR pathway, despite low plasma concentrations of nilotinib. Consequently, nilotinib‐induced hypercholesterolaemia could not be predicted based on the plasma concentration of nilotinib.

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Section: Discussioncontrasting

confidence: 85%

Effects of proprotein convertase subtilisin/kexin type 9 and nilotinib plasma concentrations on nilotinib‐induced hypercholesterolaemia in patients with chronic myeloid leukaemia

et al. 2020

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“…One more benefit of LA on circulating LDL-cholesterol is its inhibitory effect on proprotein convertase subtilisin kexin type 9 (PCSK9) [ 30 ], which directly interacts with LDLR [ 31 ]. Secreted PCSK9 binds to LDLR, promoting its internalization.…”

Section: Omega-6 Pufas and Human Healthmentioning

confidence: 99%

Beneficial Outcomes of Omega-6 and Omega-3 Polyunsaturated Fatty Acids on Human Health: An Update for 2021

2021

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Oxidative stress and inflammation have been recognized as important contributors to the risk of chronic non-communicable diseases. Polyunsaturated fatty acids (PUFAs) may regulate the antioxidant signaling pathway and modulate inflammatory processes. They also influence hepatic lipid metabolism and physiological responses of other organs, including the heart. Longitudinal prospective cohort studies demonstrate that there is an association between moderate intake of the omega-6 PUFA linoleic acid and lower risk of cardiovascular diseases (CVDs), most likely as a result of lower blood cholesterol concentration. Current evidence suggests that increasing intake of arachidonic acid (up to 1500 mg/day) has no adverse effect on platelet aggregation and blood clotting, immune function and markers of inflammation, but may benefit muscle and cognitive performance. Many studies show that higher intakes of omega-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with a lower incidence of chronic diseases characterized by elevated inflammation, including CVDs. This is because of the multiple molecular and cellular actions of EPA and DHA. Intervention trials using EPA + DHA indicate benefit on CVD mortality and a significant inverse linear dose–response relationship has been found between EPA + DHA intake and CVD outcomes. In addition to their antioxidant and anti-inflammatory roles, omega-3 fatty acids are considered to regulate platelet homeostasis and lower risk of thrombosis, which together indicate their potential use in COVID-19 therapy.

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“…The PCSK9-LDLR PPI interface was initially large and flat (Figure 4A), which was difficult and not suitable for discovering small molecule inhibitors. The virtual screening attempts directly and rigidly based on the original surface failed to identify a PCSK9-LDLR inhibitor in the reported study 41 and our previous attempts. Usually, a "pocket" is needed for the binding of small molecules to the target protein.…”

Section: ■ Results and Discussionmentioning

confidence: 66%

Discovery of Novel Small Molecule Inhibitors Disrupting the PCSK9-LDLR Interaction

Sun

Wang

Liu

et al. 2021

J. Chem. Inf. Model.

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Proprotein convertase subtilisin kexin 9 (PCSK9) has been identified as a reliable therapeutic target for hypercholesterolemia and coronary artery heart diseases since the monoclonal antibodies of PCSK9 have launched. Disrupting the protein–protein interaction (PPI) between PCSK9 and the low-density lipoprotein receptor (LDLR) has been considered as a promising approach for developing PCSK9 inhibitors. However, PPIs have been traditionally considered difficult to target by small molecules since the PPI surface is usually large, flat, featureless, and without a “pocket” or “groove” for ligand binding. The PCSK9-LDLR PPI interface is such a typical case. In this study, a potential binding pocket was generated on the PCSK9-LDLR PPI surface of PCSK9 through induced-fit docking. On the basis of this induced binding pocket, virtual screening, molecular dynamics (MD) simulation, and biological evaluations have been applied for the identification of novel small molecule inhibitors of PCSK9-LDLR PPI. Among the selected compounds, compound 13 exhibited certain PCSK9-LDLR PPI inhibitory activity (IC50: 7.57 ± 1.40 μM). The direct binding affinity between 13 and PCSK9 was determined with a K D value of 2.50 ± 0.73 μM. The LDLR uptake function could be also restored to a certain extent by 13 in HepG2 cells. This well-characterized hit compound will facilitate the further development of novel small molecule inhibitors of PCSK9-LDLR PPI.

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A small molecule inhibitor of PCSK9 that antagonizes LDL receptor binding via interaction with a cryptic PCSK9 binding groove

Cited by 36 publications

References 40 publications

Effects of proprotein convertase subtilisin/kexin type 9 and nilotinib plasma concentrations on nilotinib‐induced hypercholesterolaemia in patients with chronic myeloid leukaemia

Effects of proprotein convertase subtilisin/kexin type 9 and nilotinib plasma concentrations on nilotinib‐induced hypercholesterolaemia in patients with chronic myeloid leukaemia

Beneficial Outcomes of Omega-6 and Omega-3 Polyunsaturated Fatty Acids on Human Health: An Update for 2021

Discovery of Novel Small Molecule Inhibitors Disrupting the PCSK9-LDLR Interaction

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