Hypecotumines A-D, New Isoquinoline Alkaloids with Potential PCSK9 Inhibition Activity from Hypecoum Erectum L

Overview

Journal Nat Prod Bioprospect

Publisher Springer

Specialty Biology

Date 2024 Oct 15

PMID 39404968

Authors

Yinling Wei

Hongyan Wen

Lian Yang

Bodou Zhang

Xiaoyu Li

Sheng Li

Jing Dong

Zhenzhen Liang

Yu Zhang

Affiliations

Soon will be listed here.

Abstract

Four new isoquinoline alkaloids, hypecotumines A-D (1-4), were isolated and identified from the whole herbs of Hypecoum erectum L. Their structures were determined by a combination of HRESIMS, NMR, and X-ray diffraction analysis methods. Compounds 1-4 were characterized by a terminal double bond at C-9 and their plausible biosynthetic pathway was hypothesized. Since PCSK9 plays a key role in the development of cardiovascular disease (CVD), exploration of PCSK inhibitors from natural products are beneficial for drug discovery of CVD treatment. SPR and Western blot assays showed compound 4 had PCSK9 inhibition activity with K value of 59.9 µM and thus elevated the LDLR level. Further molecular docking studies demonstrated that 4 and PCSK9 could form stable interactions via key hydrogen bonds.

References

Chen C, Liu J, Guo L, Xiong F, Ran X, Guo Y . Monoterpenoid indole alkaloid dimers from Kopsia arborea inhibit cyclin-dependent kinase 5 and tau phosphorylation. Phytochemistry. 2022; 203:113392. DOI: 10.1016/j.phytochem.2022.113392. View

Brandts J, Ray K . Novel and future lipid-modulating therapies for the prevention of cardiovascular disease. Nat Rev Cardiol. 2023; 20(9):600-616. DOI: 10.1038/s41569-023-00860-8. View

Abifadel M, Varret M, Rabes J, Allard D, Ouguerram K, Devillers M . Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003; 34(2):154-6. DOI: 10.1038/ng1161. View

Lintner N, McClure K, Petersen D, Londregan A, Piotrowski D, Wei L . Correction: Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. PLoS Biol. 2018; 16(4):e1002628. PMC: 5903592. DOI: 10.1371/journal.pbio.1002628. View

Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes E . The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012; 380(9841):581-90. PMC: 3437972. DOI: 10.1016/S0140-6736(12)60367-5. View

Guo P, Chen T, Hu X, Duan Y, Zheng L, Du G . Lindenane sesquiterpenoid dimers from Chloranthus japonicus improve LDL uptake by regulating PCSK9 and LDLR. Bioorg Chem. 2023; 142:106958. DOI: 10.1016/j.bioorg.2023.106958. View

Seidah N, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin S, Stifani S . The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A. 2003; 100(3):928-33. PMC: 298703. DOI: 10.1073/pnas.0335507100. View

Huang M, Zhou Y, Duan D, Yang C, Zhou Z, Li F . Targeting ubiquitin conjugating enzyme UbcH5b by a triterpenoid PC3-15 from Schisandra plants sensitizes triple-negative breast cancer cells to lapatinib. Cancer Lett. 2021; 504:125-136. DOI: 10.1016/j.canlet.2021.02.009. View

Won H, Son M, Pel P, Nhoek P, An C, Kim Y . Chemical constituents from with proprotein convertase subtilisin/kexin type 9 expression and secretion inhibitory activity. Org Biomol Chem. 2023; 21(13):2801-2808. DOI: 10.1039/d3ob00225j. View

10.

Xu Z, Li Z, Ren F, Gao R, Wang Z, Zhang J . The genome of Corydalis reveals the evolution of benzylisoquinoline alkaloid biosynthesis in Ranunculales. Plant J. 2022; 111(1):217-230. PMC: 7614287. DOI: 10.1111/tpj.15788. View

11.

Koo B . Statin for the primary prevention of cardiovascular disease in patients with diabetes mellitus. Diabetes Metab J. 2014; 38(1):32-4. PMC: 3950192. DOI: 10.4093/dmj.2014.38.1.32. View

12.

Mach F, Baigent C, Catapano A, Koskinas K, Casula M, Badimon L . 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019; 41(1):111-188. DOI: 10.1093/eurheartj/ehz455. View

13.

Pijlman A, Huijgen R, Verhagen S, Imholz B, Liem A, Kastelein J . Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis. 2009; 209(1):189-94. DOI: 10.1016/j.atherosclerosis.2009.09.014. View

14.

Wen H, Yuan X, Li C, Li J, Yue H . Two new isoquinoline alkaloids from Hook. f. et Thoms. Nat Prod Res. 2022; 38(8):1392-1397. DOI: 10.1080/14786419.2022.2146108. View

15.

Dang T, Chen X, Facchini P . Acetylation serves as a protective group in noscapine biosynthesis in opium poppy. Nat Chem Biol. 2014; 11(2):104-6. DOI: 10.1038/nchembio.1717. View

16.

Yuan H, Zhao Y, Qin X, Liu Y, Yang X, Luo X . Diverse isoquinolines with anti-inflammatory and analgesic bioactivities from Hypecoum erectum. J Ethnopharmacol. 2021; 270:113811. DOI: 10.1016/j.jep.2021.113811. View

17.

Sun P, Cao Y, Xue G, Li M, Zhang C, Zhao F . Hypeisoxazole A, a Racemic Pair of Tetrahydroisoxazole-Fused Benzylisoquinoline Alkaloids from and Structural Revision of Hypecoleptopine. Org Lett. 2022; 24(7):1476-1480. PMC: 10430687. DOI: 10.1021/acs.orglett.2c00096. View

18.

Petrilli W, Adam G, Erdmann R, Abeywickrema P, Agnani V, Ai X . From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9. Cell Chem Biol. 2019; 27(1):32-40.e3. DOI: 10.1016/j.chembiol.2019.10.002. View

19.

Wei Y, Li S, Wen H, Dong J, Liang Z, Li X . H NMR guided isolation of 3-arylisoquinoline alkaloids from Hypecoum erectum L. and their anti-inflammation activity. Phytochemistry. 2024; 222:114093. DOI: 10.1016/j.phytochem.2024.114093. View

20.

Piper D, Jackson S, Liu Q, Romanow W, Shetterly S, Thibault S . The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure. 2007; 15(5):545-52. DOI: 10.1016/j.str.2007.04.004. View