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PCSK9 CTD fragment structure
Structural highlights
DiseasePCSK9_HUMAN Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:603776. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.[1] FunctionPCSK9_HUMAN Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.[2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedBACKGROUND: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is an effective therapy for reducing low-density lipoprotein (LDL) cholesterol (LDL-C) in adults with hyperlipidemia, including heterozygous familial hypercholesterolemia, thereby lowering cardiovascular risk. Current PCSK9 inhibitors are injectable therapies; no oral small-molecule PCSK9 inhibitor has yet been approved. METHODS: Laroprovstat (AZD0780) is a novel small-molecule identified through structure-based design that binds to the PCSK9 C-terminal domain. The effects of laroprovstat on LDL receptor expression and LDL-C levels were assessed in vitro and in mice expressing human PCSK9. Safety, tolerability, and pharmacokinetic and pharmacodynamic properties of laroprovstat were assessed in healthy participants with LDL-C >/=70 and </=190 mg/dL after single ascending doses. Laroprovstat was also assessed in participants with LDL-C >/=100 and </=190 mg/dL at doses of 1 mg or 30 mg versus placebo administered once daily for 28 days after a rosuvastatin 20 mg run-in treatment period. RESULTS: Laroprovstat does not inhibit the PCSK9-LDL receptor interaction but stabilizes the PCSK9 C-terminal domain, preventing lysosomal trafficking and degradation of LDL receptor. Laroprovstat increased LDL receptor expression and reduced LDL-C levels in mice expressing human PCSK9. Laroprovstat displayed dose-proportional pharmacokinetics and a half-life suitable for once-daily dosing ( approximately 40 hours). There was no clinically meaningful change in exposure when dosed with a high-fat meal compared with the fasted state (AUC(inf) and C(max) geometric mean reduction of 1.15 [90% CI, 1.11-1.19] and 1.06 [90% CI, 1.00-1.13], respectively). After a rosuvastatin 20 mg 3-week run-in treatment period, laroprovstat 1 and 30 mg reduced LDL-C by 29% (95% CI, 38%-18%) and 51% (95% CI, 58%-44%) compared with baseline. Combined rosuvastatin and laroprovstat treatment resulted in a total approximate reduction in LDL-C of 70% and 80% for laroprovstat 1 and 30 mg, respectively. CONCLUSIONS: Laroprovstat was well tolerated with no safety findings of concern and may be dosed with or without food. In treatment-naive participants with hypercholesterolemia, combined rosuvastatin 20 mg and laroprovstat 30 mg treatment led to an 80% LDL-C reduction, supporting further development of laroprovstat as the first oral small-molecule PCSK9 inhibitor in patients with hypercholesterolemia. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05384262. Laroprovstat, the First Oral Small-Molecule PCSK9 Inhibitor for the Treatment of Hypercholesterolemia: Results From a Randomized, Single-Blind, Placebo-Controlled Phase 1 Trial in Treatment-Naive Patients.,Vega RB, O'Mahony G, Barbour AM, Yu H, Knochel J, Brengdahl J, Hochdorfer T, Bergenholm L, Toppner Carlsson E, Ahnmark A, Underwood CR, Rudvik A, Carter D, Laru J, Gutgsell A, Twaddle L, Garkaviy P, Bogstedt A, Hurt-Camejo E, Miliotis T, Ryaboshapkina M, Hober A, Hubbard B, Serrano-Wu M, Kaushik V, Geschwindner S, McCarthy MC, Linden D, Rosenmeier JB Circulation. 2026 May 15. doi: 10.1161/CIRCULATIONAHA.125.075973. PMID:42137960[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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