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Peptidyl-prolyl isomerases: functionality and potential therapeutic targets in cardiovascular disease

Rostam MA, Piva TJ, Rezaei HB, Kamato D, Little PJ, Zheng W, et al.

Clin Exp Pharmacol Physiol, 2015 Feb;42(2):117-24.
PMID: 25377120 DOI: 10.1111/1440-1681.12335

Peptidyl-prolyl cis/trans isomerases (PPIases) are a conserved group of enzymes that catalyse the conversion between cis and trans conformations of proline imidic peptide bonds. These enzymes play critical roles in regulatory mechanisms of cellular function and pathophysiology of disease. There are three different classes of PPIases and increasing interest in the development of specific PPIase inhibitors. Cyclosporine A, FK506, rapamycin and juglone are known PPIase inhibitors. Herein, we review recent advances in elucidating the role and regulation of the PPIase family in vascular disease. We focus on peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1), an important member of the PPIase family that plays a role in cell cycle progression, gene expression, cell signalling and cell proliferation. In addition, Pin1 may be involved in atherosclerosis. The unique role of Pin1 as a molecular switch that impacts on multiple downstream pathways necessitates the evaluation of a highly specific Pin1 inhibitor to aid in potential therapeutic drug discovery.

Matched MeSH terms: Protein Binding/physiology
In silico and BSA binding study of some new biological analogs of 1,2,4-triazolependant with azinane through microwave and conventional synthesis

Virk NA, Rehman A, Abbasi MA, Siddiqui SZ, Ashraf A, Lateef M, et al.

Pak J Pharm Sci, 2018 Nov;31(6 (Supplementary):2645-2654.
PMID: 30587474

Microwave and conventional techniques were employed to synthesize a novel array of compounds 7a-g with 1,2,4-triazole and piperidine rings having great biological importance. The microwave assisted method has a better operational scope with respect to time and yield comparative to the conventional method. 1H-NMR, 13C-NMR and IR techniques were employed to justify the structure of synthesized compounds. The antioxidant, butyrylcholinesterase inhibition and urease inhibition potential of every synthesized compound was evaluated. Every member of the synthesized series was found potent against mentioned activities. Compound 7g was the most active anti-urease agent having IC50 (μM) value 16.5±0.09 even better than the thiourea with an IC50(μM) value of 24.3±0.24. The better urease inhibition potential of 7g was also elaborated and explained by docking and bovine serum albumin (BSA) binding studies.

Matched MeSH terms: Protein Binding/physiology
Fulltext Synthesis of novel cytotoxic tetracyclic acridone derivatives and study of their molecular docking, ADMET, QSAR, bioactivity and protein binding properties

Veligeti R, Madhu RB, Anireddy J, Pasupuleti VR, Avula VKR, Ethiraj KS, et al.

Sci Rep, 2020 11 26;10(1):20720.
PMID: 33244007 DOI: 10.1038/s41598-020-77590-1

Acridone based synthetic and natural products with inherent anticancer activity advancing the research and generating a large number of structurally diversified compounds. In this sequence we have designed, synthesized a series of tetracyclic acridones with amide framework viz., 3-(alkyloyl/ aryloyl/ heteroaryloyl/ heteroaryl)-2,3-dihydropyrazino[3,2,1-de]acridin-7(1H)-ones and screened for their in vitro anti-cancer activity. The in vitro study revealed that compounds with cyclopropyl-acetyl, benzoyl, p-hydroxybenzoyl, p-(trifluoromethyl)benzoyl, p-fluorobenzoyl, m-fluorobenzoyl, picolinoyl, 6-methylpicolinoyl and 3-nicotinoyl groups are active against HT29, MDAMB231 and HEK293T cancer cell lines. The molecular docking studies performed for them against 4N5Y, HT29 and 2VWD revealed the potential ligand-protein binding interactions among the neutral aminoacid of the enzymes and carbonyl groups of the title compounds with a binding energy ranging from - 8.1394 to - 6.9915 kcal/mol. In addition, the BSA protein binding assay performed for them has confirmed their interaction with target proteins through strong binding to BSA macromolecule. The additional studies like ADMET, QSAR, bioactivity scores, drug properties and toxicity risks ascertained them as newer drug candidates. This study had added a new collection of piperazino fused acridone derivatives to the existing array of other nitrogen heterocyclic fused acridone derivatives as anticancer agents.

Matched MeSH terms: Protein Binding/physiology*
Interferon-γ induces biphasic changes in caldesmon localization as well as adherens junction organization and expression in HUVECs

Ng CT, Fong LY, Yong YK, Hakim MN, Ahmad Z

Cytokine, 2018 11;111:541-550.
PMID: 29909980 DOI: 10.1016/j.cyto.2018.06.010

Endothelial barrier dysfunction leads to increased endothelial permeability and is an early step in the development of vascular inflammatory diseases such as atherosclerosis. Interferon-γ (IFN-γ), a proinflammatory cytokine, is known to cause increased endothelial permeability. However, the mechanisms by which IFN-γ disrupts the endothelial barrier have not been clarified. This study aimed to investigate how IFN-γ impairs the endothelial barrier integrity by specifically examining the roles of caldesmon, adherens junctions (AJs) and p38 mitogen-activated protein (MAP) kinase in IFN-γ-induced endothelial barrier dysfunction. IFN-γ exhibited a biphasic effect on caldesmon localization and both the structural organization and protein expression of AJs. In the early phase (4-8 h), IFN-γ induced the formation of peripheral caldesmon bands and discontinuous AJs, while AJ protein expression was unchanged. Interestingly, IFN-γ also stimulated caldesmon phosphorylation, resulting in actin dissociation from caldesmon at 8 h. Conversely, changes seen in the late phase (16-24 h) included cytoplasmic caldesmon dispersal, AJ linearization and junctional area reduction, which were associated with reduced membrane, cytoskeletal and total AJ protein expression. In addition, IFN-γ enhanced myosin binding to caldesmon at 12 h and persisted up to 24 h. Furthermore, inhibition of p38 MAP kinase by SB203580 did not reverse either the early or late phase changes observed. These data suggest that IFN-γ may activate signaling molecules other than p38 MAP kinase. In conclusion, our findings enhance the current understanding of how IFN-γ disrupts endothelial barrier function and reveal potential therapeutic targets, such as caldesmon and AJs, for the treatment of IFN-γ-associated vascular inflammatory diseases.

Matched MeSH terms: Protein Binding/physiology
Molecular mechanism of L-SP40 peptide and in vivo efficacy against EV-A71 in neonatal mice

Lalani S, Tan SH, Tan KO, Lim HX, Ong KC, Wong KT, et al.

Life Sci, 2021 Dec 15;287:120097.
PMID: 34715144 DOI: 10.1016/j.lfs.2021.120097

AIMS: Enterovirus A71 (EV-A71) is an etiological agent of hand foot and mouth disease (HFMD) and has the potential to cause severe neurological infections in children. L-SP40 peptide was previously known to inhibit EV-A71 by prophylactic action. This study aimed to identify the mechanism of inhibition in Rhabdomyosarcoma (RD) cells and in vivo therapeutic potential of L-SP40 peptide in a murine model.
MAIN METHODS: A pull-down assay was performed to identify the binding partner of the L-SP40 peptide. Co-immunoprecipitation and co-localization assays with the L-SP40 peptide were employed to confirm the receptor partner in RD cells. The outcomes were validated using receptor knockdown and antibody blocking assays. The L-SP40 peptide was further evaluated for the protection of neonatal mice against lethal challenge by mouse-adapted EV-A71.
KEY FINDINGS: The L-SP40 peptide was found to interact and co-localize with nucleolin, the key attachment receptor of Enteroviruses A species, as demonstrated in the pull-down, co-immunoprecipitation and co-localization assays. Knockdown of nucleolin from RD cells led to a significant reduction of 3.5 logs of viral titer of EV-A71. The L-SP40 peptide demonstrated 80% protection of neonatal mice against lethal challenge by the mouse-adapted virus with a drastic reduction in the viral loads in the blood (~4.5 logs), skeletal muscles (1.5 logs) and brain stem (1.5 logs).
SIGNIFICANCE: L-SP40 peptide prevented severe hind limb paralysis and death in suckling mice and could serve as a potential broad-spectrum antiviral candidate to be further evaluated for safety and potency in future clinical trials against EV-A71.

Matched MeSH terms: Protein Binding/physiology
Fulltext Molecular modeling, dynamics simulations, and binding efficiency of berberine derivatives: A new group of RAF inhibitors for cancer treatment

Jabbarzadeh Kaboli P, Ismail P, Ling KH

PLoS One, 2018;13(3):e0193941.
PMID: 29565994 DOI: 10.1371/journal.pone.0193941

RAF kinases are a family of enzymes in the MAP kinase pathway that contribute to the development of different types of cancer. BRAF is the most important member of RAF kinases. BRAF mutations have been detected in 7% of all cancers and 66% of melanomas; as such, the FDA has approved a few BRAF inhibitor drugs to date. However, BRAF can activate CRAF leading to resistance to BRAF inhibitors. Berberine (BBR) is an alkaloid that is widely distributed in different plant species. Several studies have been carried out on the anti-cancer effects of BBR but direct targets of BBR are unknown. In this study, interactions of BBR derivatives against BRAF and CRAF kinases were modeled and predicted using an in silico-based approach. To analyze and identify the residues important in BRAF docking, we modeled interactions of ATP, the universal substrate of BRAF, and found that Lys483 and Asp594 are the most important residues involved in both ATP and BBR binding [(The average score = -11.5 kcal/mol (ATP); Range of scores = -7.78 to -9.55 kcal/mol (BBR)]. In addition to these polar residues, Trp530 and Phe583 are also applicable to the molecular docking of BRAF. We also observed that Asp593 was excluded from the enzyme cavity, while Phe594 was included inside the cavity, making the enzyme inactive. Finally, three alternatives for BBR were identified with dual RAF inhibition effects [The best scores against BRAF = -11.62 kcal/mol (BBR-7), -10.64 kcal/mol (BBR-9), and -11.01 kcal/mol (BBR-10); the best scores against CRAF = -9.68 kcal/mol (BBR-7), -9.60 kcal/mol (BBR-9), and -9.20 kcal/mol (BBR-10)]. Direct effects of BBR derivatives against BRAF and CRAF kinases had not yet been reported previously, and, thus, for the first time, we report three cycloprotoberberines as lead compounds against RAF kinases.

Matched MeSH terms: Protein Binding/physiology*