Biomedicines

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Dear Colleagues,

Since its seminal discovery in 2003, proprotein convertase subtilisin/kexin type-9 (PCSK9) has transcended from its initial role in lipid homeostasis into becoming a pivotal player in a wide range of human diseases. Initially identified for its role in regulating cholesterol levels by targeting low-density lipoprotein (LDL) receptors for degradation, PCSK9 inhibitors, including evolocumab and alirocumab, have revolutionized cardiovascular medicine as the next line of therapy in cholesterol lowering and provided new hope for patients with familial hypercholesterolemia.

Beyond lipid management, others have unveiled PCSK9's involvement in a myriad of diseases. This includes the modulation of the immune system, impacting inflammatory conditions such as rheumatoid arthritis and psoriasis. In neurology, PCSK9 inhibition shows promise for neurodegenerative disorders, such as Alzheimer's disease, by enhancing the clearance of amyloid-beta plaques. Moreover, cancer research has also embraced PCSK9 antagonism. Studies suggest its critical role in promoting tumor cell growth and migration, making PCSK9 a potential target for cancer therapies.

This Special Issue aims at compiling the most recent findings from PCSK9 inhibitor research and their intricate connections with human diseases that extend far beyond the realms of lipid homeostasis and atherosclerosis. Additionally, it will cover the role of PCSK9 in human cancers, neurodegenerative disorders, and the immune system's involvement in complex pathological inflammatory processes. We hope to provide a clear outline and a foundation for future research as we continue to unravel more roles of this multifaceted protein, potentially revolutionizing treatment strategies across cardiovascular medicine and beyond.

Dr. Jae Hyun Byun
Guest Editor

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Keywords

PCSK9
cholesterol
cardiovascular diseases
neurological diseases
human cancer
inflammation
anti-PCSK9 therapies
siRNA
monoclonal antibodies
genetics

Published Papers (1 paper)

Research

19 pages, 5743 KiB

Open AccessArticle

Targeting Allosteric Site of PCSK9 Enzyme for the Identification of Small Molecule Inhibitors: An In Silico Drug Repurposing Study

by Nitin Bharat Charbe, Flavia C. Zacconi, Venkata Krishna Kowthavarapu, Churni Gupta, Sushesh Srivatsa Palakurthi, Rajendran Satheeshkumar, Deepak K. Lokwani, Murtaza M. Tambuwala and Srinath Palakurthi

Biomedicines 2024, 12(2), 286; https://doi.org/10.3390/biomedicines12020286 - 26 Jan 2024

Cited by 1 | Viewed by 1224

Abstract

The primary cause of atherosclerotic cardiovascular disease (ASCVD) is elevated levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in this process by binding to the LDL receptor (LDL-R) domain, leading to reduced influx of LDL-C and decreased LDL-R cell surface presentation on hepatocytes, resulting higher circulating levels of LDL-C. As a consequence, PCSK9 has been identified as a crucial target for drug development against dyslipidemia and hypercholesterolemia, aiming to lower plasma LDL-C levels. This research endeavors to identify promising inhibitory candidates that target the allosteric site of PCSK9 through an in silico approach. To start with, the FDA-approved Drug Library from Selleckchem was selected and virtually screened by docking studies using Glide extra-precision (XP) docking mode and Smina software (Version 1.1.2). Subsequently, rescoring of 100 drug compounds showing good average docking scores were performed using Gnina software (Version 1.0) to generate CNN Score and CNN binding affinity. Among the drug compounds, amikacin, bestatin, and natamycin were found to exhibit higher docking scores and CNN affinities against the PCSK9 enzyme. Molecular dynamics simulations further confirmed that these drug molecules established the stable protein–ligand complexes when compared to the apo structure of PCSK9 and the complex with the co-crystallized ligand structure. Moreover, the MM-GBSA calculations revealed binding free energy values ranging from −84.22 to −76.39 kcal/mol, which were found comparable to those obtained for the co-crystallized ligand structure. In conclusion, these identified drug molecules have the potential to serve as inhibitors PCSK9 enzyme and these finding could pave the way for the development of new PCSK9 inhibitory drugs in future in vitro research. Full article

(This article belongs to the Special Issue The Role of PCSK9 and Its Antagonism in Human Disease)

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