Targeting PCSK9 to tackle cardiovascular disease

Hummelgaard, Sandra; Vilstrup, Joachim; Gustafsen, Camilla; Glerup, Simon; Weyer, Kathrin

doi:10.1016/j.pharmthera.2023.108480

Cited by 19 publications

(13 citation statements)

References 221 publications

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Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

“…PCSK9 is a serine protease consisting of four parts: a signal peptide, a prestructural domain, a catalytic structural domain, and a C‐terminal cysteine/histidine‐rich structural domain, 65,66 which is mainly produced by the liver and secreted into the bloodstream 67 . In addition, there is low expression in the intestinal tract, central nervous system, and renal mesenchymal stromal cells 67,68 . The link between PCSK9 and cholesterol metabolism was first identified in PCSK9‐overexpressing wild‐type mice, 67 which had increased plasma triglyceride (TG) and cholesterol‐rich LDL (LDL‐C) levels, whereas hepatic low‐density lipoprotein receptor (LDLR) was virtually absent 67 .…”

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

“…In addition, there is low expression in the intestinal tract, central nervous system, and renal mesenchymal stromal cells 67,68 . The link between PCSK9 and cholesterol metabolism was first identified in PCSK9‐overexpressing wild‐type mice, 67 which had increased plasma triglyceride (TG) and cholesterol‐rich LDL (LDL‐C) levels, whereas hepatic low‐density lipoprotein receptor (LDLR) was virtually absent 67 . In contrast, PCSK9 KO mice had reduced plasma cholesterol levels and increased hepatic LDLR 67 .…”

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

“…The link between PCSK9 and cholesterol metabolism was first identified in PCSK9‐overexpressing wild‐type mice, 67 which had increased plasma triglyceride (TG) and cholesterol‐rich LDL (LDL‐C) levels, whereas hepatic low‐density lipoprotein receptor (LDLR) was virtually absent 67 . In contrast, PCSK9 KO mice had reduced plasma cholesterol levels and increased hepatic LDLR 67 . The understanding of the physiological function of PCSK9 in humans initially arose from the discovery that functional mutations in the PCSK9 gene resulted in dominant familial hypercholesterolemia (FH) 21 .…”

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

“…WES of university students from Uyghur and other ethnic groups in Xinjiang, China, revealed that PCSK9 LOFs (E144K and C378W) were associated with low plasma levels of LDL‐C 79 . With the increasing sophistication of genetic testing methods (e.g., WES and WGS), multiple GOF or LOF mutations in PCSK9 have been found to be associated with hypercholesterolemia or hypocholesterolemia 67,76,80,81 …”

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

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Drug development advances in human genetics‐based targets

Zhang,

Yu,

et al. 2024

MedComm

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Drug development is a long and costly process, with a high degree of uncertainty from the identification of a drug target to its market launch. Targeted drugs supported by human genetic evidence are expected to enter phase II/III clinical trials or be approved for marketing more quickly, speeding up the drug development process. Currently, genetic data and technologies such as genome‐wide association studies (GWAS), whole‐exome sequencing (WES), and whole‐genome sequencing (WGS) have identified and validated many potential molecular targets associated with diseases. This review describes the structure, molecular biology, and drug development of human genetics‐based validated beneficial loss‐of‐function (LOF) mutation targets (target mutations that reduce disease incidence) over the past decade. The feasibility of eight beneficial LOF mutation targets (PCSK9, ANGPTL3, ASGR1, HSD17B13, KHK, CIDEB, GPR75, and INHBE) as targets for drug discovery is mainly emphasized, and their research prospects and challenges are discussed. In conclusion, we expect that this review will inspire more researchers to use human genetics and genomics to support the discovery of novel therapeutic drugs and the direction of clinical development, which will contribute to the development of new drug discovery and drug repurposing.

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Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

See 3 more Smart Citations

Drug development advances in human genetics‐based targets

Zhang,

Yu,

et al. 2024

MedComm

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Phytochemical Analysis and Anti‐dyslipidemia and Antioxidant Activities of Pluchea dioscoridis: In Vitro, In Silico and In Vivo Studies

Sultan,

Mahmoud,

Ahmed

et al. 2024

Chemistry & Biodiversity

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Pluchea dioscoridis is a flowering wild plant used traditionally in the treatment of rhematic disorders. This study investigated the phytochemical and in vitro radical scavenging activity (RSA), and in vivo anti‐hyperlipidemic, antioxidant and anti‐inflammatory properties of P. dioscoridis. The antihyperlipidemic efficacy was determined in a rat model of dyslipidemia. The extract and fractions of P. dioscoridis showed RSA with the EA fraction, exhibiting the most potent activity. The Phytochemical analysis of P. dioscoridis EA fraction (PDEAF) led to the isolation of five compounds (lupeol, quercetin, lupeol acetate, stigmasterol, and syringic acid). To evaluate its anti‐hyperlipidemic effect, dyslipidemia three doses of PDEAF were supplemented to rats for 14 days and poloxamer‐407 was administered on day 15 to induce dyslipidemia. All doses of PDEAF decreased plasma triglycerides, cholesterol, LDL and vLDL, and increased plasma LPL. PDEAF upregulated hepatic LDL receptor and suppressed HMG‐CoA reductase, decreased lipid peroxidation and TNF‐α and enhanced GSH and enzymatic antioxidants in dyslipidmeic rats. In silico findings revealed the binding affinity of the isolated compounds towards LPL, HMG‐CoA reductase, and LDL receptor. In conclusion, P. dioscoridis is rich in phytoconstituents, exhibited RSA and its EA fraction effectively prevented acute dyslipidemia and its associated oxidative stress and inflammatory response.

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