Development of small-molecule PCSK9 inhibitors for the treatment of hypercholesterolemia

Ahamad, Shakir; Mathew, Shintu; Khan, Waqas Ahmad; Mohanan, Kishor

doi:10.1016/j.drudis.2022.01.014

Cited by 31 publications

(46 citation statements)

References 120 publications

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“…Cost-effective small-molecules with specific PCSK9 inhibition activity is an attractive research field. The advances of these inhibitors including derivatives of guanidine, berberine, piperidine, imidazole, and benzimidazole, have been well-documented recently by Ahamad et al (2022) . Of note, accumulating evidence have demonstrated that natural products are an important resource for discovery of PCSK9i.…”

Section: Therapies Targeting Ldl-pmentioning

confidence: 99%

“…Of note, accumulating evidence have demonstrated that natural products are an important resource for discovery of PCSK9i. These natural products include berberine, lupin, quercetin, resveratrol, and others as reviewed by several groups ( Ahamad et al, 2022 ; Waiz et al, 2022 ). Mechanistically, these small molecules may directly inhibit PCSK9-LDLR interactions, PCSK9 production, transcription, and secretion ( Ahamad et al, 2022 ).…”

Section: Therapies Targeting Ldl-pmentioning

confidence: 99%

“…These natural products include berberine, lupin, quercetin, resveratrol, and others as reviewed by several groups ( Ahamad et al, 2022 ; Waiz et al, 2022 ). Mechanistically, these small molecules may directly inhibit PCSK9-LDLR interactions, PCSK9 production, transcription, and secretion ( Ahamad et al, 2022 ). Although some advances have been achieved, none of these small-molecule PCSK9i has been approved by the Food and Drug Administration of any country.…”

Section: Therapies Targeting Ldl-pmentioning

confidence: 99%

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Low-density lipoprotein particles in atherosclerosis

2022

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Among the diseases causing human death, cardiovascular disease (CVD) remains number one according to the World Health Organization report in 2021. It is known that atherosclerosis is the pathological basis of CVD. Low-density lipoprotein (LDL) plays a pivotal role in the initiation and progression of atherosclerotic CVD (ASCVD). LDL cholesterol (LDL-C) is the traditional biological marker of LDL. However, large numbers of patients who have achieved the recommended LDL-C goals still have ASCVD risk. In multiple prospective studies, LDL particle (LDL-P) is reported to be more accurate in predicting CVD risk than LDL-C. LDL-Ps differ in size, density and chemical composition. Numerous clinical studies have proved that the atherogenic mechanisms of LDL-Ps are determined not only by LDL number and size but also by LDL modifications. Of note, small dense LDL (sdLDL) particles possess stronger atherogenic ability compared with large and intermediate LDL subfractions. Besides, oxidized LDL (ox-LDL) is another risk factor in atherosclerosis. Among the traditional lipid-lowering drugs, statins induce dramatic reductions in LDL-C and LDL-P to a lesser extend. Recently, proprotein convertase subtilsin/kexin type 9 inhibitors (PCSK9i) have been demonstrated to be effective in lowering the levels of LDL-C, LDL-P, as well as CVD events. In this article, we will make a short review of LDL metabolism, discuss the discordance between LDL-C and LDL-P, outline the atherogenic mechanisms of action of LDL by focusing on sdLDL and ox-LDL, summarize the methods used for measurement of LDL subclasses, and conclude the advances in LDL-lowering therapies using statins and PCSK9i.

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Section: Therapies Targeting Ldl-pmentioning

confidence: 99%

Section: Therapies Targeting Ldl-pmentioning

confidence: 99%

Section: Therapies Targeting Ldl-pmentioning

confidence: 99%

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Low-density lipoprotein particles in atherosclerosis

2022

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“…Small-molecule drugs mainly refer to organic compounds with molecular weights less than 1000, and they have been widely used and mature in theory [ 113 , 114 , 115 , 116 , 117 ]. Apixaban, widely used in clinical practice, is a small molecule drug whose main mechanism is to inhibit the expression of FXa [ 118 , 119 , 120 , 121 , 122 ].…”

Section: Small Molecule Drugs Targeting Hif To Inhibit Gastric Cancermentioning

confidence: 99%

HIF in Gastric Cancer: Regulation and Therapeutic Target

Guan

Yang

et al. 2022

Molecules

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HIF means hypoxia-inducible factor gene family, and it could regulate various biological processes, including tumor development. In 2021, the FDA approved the new drug Welireg for targeting HIF-2a, and it is mainly used to treat von Hippel-Lindau syndrome, which demonstrated its good prospects in tumor therapy. As the fourth deadliest cancer worldwide, gastric cancer endangers the health of people all across the world. Currently, there are various treatment methods for patients with gastric cancer, but the five-year survival rate of patients with advanced gastric cancer is still not high. Therefore, here we reviewed the regulatory role and target role of HIF in gastric cancer, and provided some references for the treatment of gastric cancer.

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“…More and more approaches are being developed for new classes of drugs that influence the reduction in LDL-C through the novel mechanism and are under evaluation due to the high cost of PCSK-9 inhibitors. CRISPR-based gene editing is a technology that can modulate PCSK-9 expression through genome editing [ 94 , 95 ]. Other therapeutic options are adnectins and anticalins that inhibit the interaction between the PCSK-9 protein and LDL-R [ 95 , 96 , 97 ].…”

Section: New Approaches For Pcsk-9 Inhibitionmentioning

confidence: 99%

Recent Advances on the Roles of PCSK-9 Inhibitors in the Management of Acute Ischemic Stroke Patients

Iluţ

Pirlog

Pîrlog

et al. 2022

IJMS

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Acute ischemic stroke (AIS) represents an important cause of disability and death. Since only a minor percentage of patients with AIS are eligible for acute therapy, the management of risk factors is mandatory. An important risk factor of AIS is hyperlipemia. The current guidelines recommend a strict correction of it. Statins are recommended as the first-line treatment, while proprotein convertase subtilin/kexin type 9 (PCSK-9) inhibitors are administered as a second or even third option when the goal for a low-density lipoprotein cholesterol (LDL-C) level is not achieved. PCSK-9 inhibitors effectively decrease the LDL-C levels through the inhibition of PCSK-9-LDL-receptor complex formation. The in-depth understanding of the PCSK-9 protein mechanism in the metabolism of LDL-C led to the development of effective targeted approaches. Furthermore, a better understanding of the LDL-C metabolic pathway led to the development of newer approaches, which increased the therapeutic options. This article aims to offer an overview of the PCSK-9 inhibitors and their mechanism in reducing the LDL-C levels. Moreover, we will present the main indications of the current guidelines for patients with hyperlipemia and for those who have suffered an acute ischemic stroke, as well as the importance of LDL-C reduction in decreasing the rate of a recurrence.

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Development of small-molecule PCSK9 inhibitors for the treatment of hypercholesterolemia

Cited by 31 publications

References 120 publications

Low-density lipoprotein particles in atherosclerosis

Low-density lipoprotein particles in atherosclerosis

HIF in Gastric Cancer: Regulation and Therapeutic Target

Recent Advances on the Roles of PCSK-9 Inhibitors in the Management of Acute Ischemic Stroke Patients

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