Targeting RIPK1 kinase for modulating inflammation in human diseases

Li, Wanjin; Yuan, Junying

doi:10.3389/fimmu.2023.1159743

Cited by 20 publications

(8 citation statements)

References 153 publications

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“…Recent preclinical and clinical studies have unquestionably recognized the roles of RIPK1 in neurogenerative disorders ( Li & Yuan, 2023 ; Scarpellini et al, 2023 ; Xu, Zhang & Zhuang, 2023 ). In a phase I clinical trial, a small molecule GFH312 showed significant RIPK1 inhibition with a tolerability profile comparable to that of the placebo ( Lickliter et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

“…It has been extensively studied in the context of necroptosis, a programmed form of necrosis triggered by death-domain receptors (DRs) and executed in the absence of caspase activity. RIPK1 inhibition has emerged as a prime target in various neurodegenerative disorders, including AD, PD, and HD ( Degterev, Ofengeim & Yuan, 2019 ; Li & Yuan, 2023 ; Xu, Zhang & Zhuang, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

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Virtual screening of flavonoids as potential RIPK1 inhibitors for neurodegeneration therapy

Bepari,

Shatabda,

Reza

2024

PeerJ

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Background Global prevalence of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease is increasing gradually, whereas approvals of successful therapeutics for central nervous system disorders are inadequate. Accumulating evidence suggests pivotal roles of the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in modulating neuroinflammation and necroptosis. Discoveries of potent small molecule inhibitors for RIPK1 with favorable pharmacokinetic properties could thus address the unmet medical needs in treating neurodegeneration. Methods In a structure-based virtual screening, we performed site-specific molecular docking of 4,858 flavonoids against the kinase domain of RIPK1 using AutoDock Vina. We predicted physicochemical descriptors of the top ligands using the SwissADME webserver. Binding interactions of the best ligands and the reference ligand L8D were validated using replicated 500-ns Gromacs molecular dynamics simulations and free energy calculations. Results From Vina docking, we shortlisted the top 20 flavonoids with the highest binding affinities, ranging from −11.7 to −10.6 kcal/mol. Pharmacokinetic profiling narrowed down the list to three orally bioavailable and blood-brain-barrier penetrant flavonoids: Nitiducarpin, Pinocembrin 7-O-benzoate, and Paratocarpin J. Next, trajectories of molecular dynamics simulations of the top protein-ligand complexes were analyzed for binding interactions. The root-mean-square deviation (RMSD) was 1.191 Å (±0.498 Å), 1.725 Å (±0.828 Å), 1.923 Å (±0.942 Å), 0.972 Å (±0.155 Å) for Nitiducarpin, Pinocembrin 7-O-benzoate, Paratocarpin J, and L8D, respectively. The radius of gyration (Rg) was 2.034 nm (±0.015 nm), 2.0.39 nm (± 0.025 nm), 2.053 nm (±0.021 nm), 2.037 nm (±0.016 nm) for Nitiducarpin, Pinocembrin 7-O-benzoate, Paratocarpin J, and L8D, respectively. The solvent accessible surface area (SASA) was 159.477 nm2 (±3.021 nm2), 159.661 nm2 (± 3.707 nm2), 160.755 nm2 (±4.252 nm2), 156.630 nm2 (±3.521 nm2), for Nitiducarpin, Pinocembrin 7-O-benzoate, Paratocarpin J, and L8D complexes, respectively. Therefore, lower RMSD, Rg, and SASA values demonstrated that Nitiducarpin formed the most stable complex with the target protein among the best three ligands. Finally, 2D protein-ligand interaction analysis revealed persistent hydrophobic interactions of Nitiducarpin with the critical residues of RIPK1, including the catalytic triads and the activation loop residues, implicated in the kinase activity and ligand binding. Conclusion Our target-based virtual screening identified three flavonoids as strong RIPK1 inhibitors, with Nitiducarpin exhibiting the most potent inhibitory potential. Future in vitro and in vivo studies with these ligands could offer new hope for developing effective therapeutics and improving the quality of life for individuals affected by neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Virtual screening of flavonoids as potential RIPK1 inhibitors for neurodegeneration therapy

Bepari,

Shatabda,

Reza

2024

PeerJ

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“…On the one hand, UA can induce cell damage through the activation of inflammatory responses and oxidative stress. On the other hand, UA can also affect the function of the immune system, including leukocyte migration and cytokine production (6). Therefore, UA may play a role in regulating the development of sepsis-induced inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

“…This finding indicated that the initial serum UA levels during hospitalization should serve as a predictive indicator for the prognosis of sepsis in the pediatric intensive care unit (ICU) (5). Serum UA may play an important role in inflammatory responses, oxidative stress, and immune regulation (6). Inflammation caused an increase in the release of purines within cells, which in turn promoted the production and release of UA (7).…”

Section: Introductionmentioning

confidence: 99%

Causal Roles of Serum Uric Acid Levels and Gout in Sepsis: A Mendelian Randomization Study

Qin,

Yang,

Ning

2024

Shock

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Objective Several epidemiological studies have identified a potential link between serum uric acid(UA), gout and sepsis. The primary objective of this study is to delve deeper into this connection, investigating the causal effect of UA and gout on sepsis by applying Mendelian Randomization (MR). Methods The causal relationship was analyzed using data from genome-wide association study(GWAS). Inverse variance weighting (IVW) was used as the main analysis method. Three complementary methods were used for our MR analysis, which included the MR-Egger regression method, the weighted median method, the simple median method. Horizontal pleiotropy was identified by MR-Egger intercept test. Cochran’s Q statistics were employed to assess the existence of instrument heterogeneity. The leave-one-out method was used as a sensitivity analysis. Results The IVW results indicated that there was a positive causal relationship between UA and sepsis(critical care) (OR = 0.24, 95%CI: 0.04 to 0.43, P = 0.018, F = 4291.20). There was no significant association between UA and sepsis(28 day death in critical care) (OR = 0.10, 95%CI: -0.29 to 0.50, P = 0.604). There was no significant association between gout and sepsis(critical care) (OR = 0.85, 95%CI: -4.87 to 6.57, P = 0.771), and sepsis(28 day death in critical care) (OR = -6.30, 95%CI: -17.41 to 4.81, P = 0.267). Horizontal pleiotropy was absent in this study. The results were robust under all sensitivity analyses. Conclusion The study revealed that elevated UA levels was causally linked with sepsis(critical care). No causal relationship had been found between UA and sepsis(28 day death in critical care), as well as between gout and sepsis.

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“…(I) Necrostatin-1 (Nec-1) is a potent and specific small-molecule inhibitor of receptor-interacting serine/threonineprotein kinase 1 (RIPK1). RIPK1, through its kinase and scaffolding functions, is a key regulator of apoptosis, necroptosis, and inflammatory pathways [163,164]. (J) The compound z-VAD-FMK (zVAD) is a cell-permeant pan-caspase inhibitor that irreversibly binds to the catalytic site of caspase proteases and can inhibit the induction of apoptosis [165].…”

Section: Therapeutic Targeting Of Clec16amentioning

confidence: 99%

CLEC16A—An Emerging Master Regulator of Autoimmunity and Neurodegeneration

Pandey

Bakay

Hákonarson

2023

IJMS

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CLEC16A is emerging as an important genetic risk factor for several autoimmune disorders and for Parkinson disease (PD), opening new avenues for translational research and therapeutic devel-opment. While the exact role of CLEC16A in health and disease is still being elucidated, the gene plays a critical role in the regulation of autophagy, mitophagy, endocytosis, intracellular trafficking, immune function, and in biological processes such as insulin secretion and others that are important to cellular homeostasis. As shown in both human and animal modeling studies, CLEC16A hypo-function predisposes to both autoinflammatory phenotype and neurodegeneration. While the two are clearly related, further functional studies are needed to fully understand the mechanisms in-volved for optimized therapeutic interventions. Based on recent data, mitophagy-inducing drugs may be warranted, and such therapy should be tested in clinical trials as these drugs would tackle the underlying pathogenic mechanism (s) and could treat or prevent symptoms of autoimmunity and neurodegeneration in individuals with CLEC16A risk variants. Accordingly, interventions di-rected at reversing the dysregulated mitophagy and the consequences of loss of function of CLEC16A without activating other detrimental cellular pathways could present an effective ther-apy. This review presents the emerging role of CLEC16A in health and disease and provides an update on the disease processes that are attributed to variants located in the CLEC16A gene, which are responsible for autoimmune disorders and neurodegeneration with emphasis on how this in-formation is being translated into practical and effective applications in the clinic.

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Targeting RIPK1 kinase for modulating inflammation in human diseases

Cited by 20 publications

References 153 publications

Virtual screening of flavonoids as potential RIPK1 inhibitors for neurodegeneration therapy

Virtual screening of flavonoids as potential RIPK1 inhibitors for neurodegeneration therapy

Causal Roles of Serum Uric Acid Levels and Gout in Sepsis: A Mendelian Randomization Study

CLEC16A—An Emerging Master Regulator of Autoimmunity and Neurodegeneration

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