LRH-1 (liver receptor homolog-1) derived affinity peptide ligand to inhibit interactions between β-catenin and LRH-1 in pancreatic cancer cells: from computational design to experimental validation

Pouraghajan, Khadijeh; Mahdiuni, Hamid; Ghobadi, Sirous; Khodarahmi, Reza

doi:10.1080/07391102.2020.1845241

Cited by 9 publications

(11 citation statements)

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“…Further analyses were performed between 10 and 100 ns for the generated peptides/M pro simulation trajectories to acquire accurate and reproducible data where the systems were at equilibrium. Low fluctuations of RMSD are associated with greater stability of the protein structure [ 45 , 46 ]. The fluctuation of RMSD along the trajectory was found to be 0.15 to 0.25, 0.15–0.3, and ∼0.25–0.35 nm for apo M pro , 1KJ0-7/M pro and 2ERW-9/M pro complexes, respectively ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Insect protease inhibitors; promising inhibitory compounds against SARS-CoV-2 main protease

Hemmati

Tabein

2022

Computers in Biology and Medicine

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has adversely affected global health since its emergence in 2019. The lack of effective treatments prompted worldwide efforts to immediately develop therapeutic strategies against COVID-19. The main protease (M pro ) of SARS-CoV-2 plays a crucial role in viral replication, and therefore it serves as an attractive target for COVID-19-specific drug development. Due to the richness and diversity of insect protease inhibitors, we docked SARS-CoV-2 M pro onto 25 publicly accessible insect-derived protease inhibitors using the ClusPro server, and the regions with high inhibitory potentials against M pro were used to design peptides. Interactions of these inhibitory peptides with M pro were further assessed by two directed docking programs, AutoDock and Haddock. AutoDock analysis predicted the highest binding energy (−9.39 kcal/mol) and the lowest inhibition constant (130 nM) for the peptide 1KJ0-7 derived from SGCI ( Schistocerca gregaria chymotrypsin inhibitor). On the other hand, Haddock analysis resulted in the discovery of a different peptide designated 2ERW-9 from infestin, a serine protease inhibitor of Triatoma infestans , with the best docking score (−131), binding energy (−11.7 kcal/mol), and dissociation constant (2.6E-09 M) for M pro . Furthermore, using molecular dynamic simulations, 1KJ0-7 and 2ERW-9 were demonstrated to form stable complexes with M pro . The peptides also showed suitable drug-likeness properties compared to commercially available drugs based on Lipinski's rule. Our findings present two peptides with possible protease inhibitor activities against M pro and further demonstrate the potential of insect-derived peptides and computer-aided methods for drug discovery.

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Section: Resultsmentioning

confidence: 99%

Insect protease inhibitors; promising inhibitory compounds against SARS-CoV-2 main protease

Hemmati

Tabein

2022

Computers in Biology and Medicine

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“…By the use of virtual screening and modeling, PEP8 (sequence DEMEEPQQTE) was designed and confirmed to decrease expression of G1/S-specific cyclin-D1 (CCND1) by 10.8-fold, G1/S-specific cyclin-E1 (CCNE1) by 24.7-fold, and Myc proto-oncogene protein (c-myc) by 4.8-fold in AsPC-1 cells. This alternative approach to modulate LRH-1 only inhibits signaling through the Wnt pathway and may be an attractive avenue for selective modulation …”

Section: Medicinal Chemistry Of Lrh-1 Ligandsmentioning

confidence: 99%

“… a From ref . b Distance between mT360/hT341 and mN438/hN419 as determined in Chimera. c From ref . d Volume of the 5 Å distance around the ligand as determined in MOE (SVL tool protein pocket volume). …”

Section: Structure and Function Of Lrh-1mentioning

confidence: 99%

“…Other LRH-1 Modulators. Pouraghajan et al 28 pursued an alternative strategy to inhibit LRH-1 activity. In pancreatic cancer cells, the effects of LRH-1 activation are mainly mediated via the Wnt-signaling pathway.…”

Section: Medicinal Chemistry Of Lrh-1 Ligandsmentioning

confidence: 99%

“…This alternative approach to modulate LRH-1 only inhibits signaling through the Wnt pathway and may be an attractive avenue for selective modulation. 28…”

Section: Medicinal Chemistry Of Lrh-1 Ligandsmentioning

confidence: 99%

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The Medicinal Chemistry and Therapeutic Potential of LRH-1 Modulators

et al. 2021

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The ligand-activated transcription factor liver receptor homologue 1 (LRH-1, NR5A2) is involved in the regulation of metabolic homeostasis, including cholesterol and glucose balance. Preliminary evidence points to therapeutic potential of LRH-1 modulation in diabetes, hepatic diseases, inflammatory bowel diseases, atherosclerosis, and certain cancers, but because of a lack of suitable ligands, pharmacological control of LRH-1 has been insufficiently studied. Despite the availability of considerable structural knowledge on LRH-1, only a few ligand chemotypes have been developed, and potent, selective, and bioavailable tools to explore LRH-1 modulation in vivo are lacking. In view of the therapeutic potential of LRH-1 in prevalent diseases, improved chemical tools are needed to probe the beneficial and adverse effects of pharmacological LRH-1 modulation in sophisticated preclinical models and to further elucidate the receptor’s molecular function.

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Loss of CBX2 causes genomic instability and Wnt activation in high grade serous ovarian carcinoma cells

Liu

Zheng

et al. 2023

Molecular Carcinogenesis

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High grade serous ovarian carcinoma (HGSOC) is lethal with insidious onset, rapid progression, poor prognosis, and limited treatment options. Polycomb repressor complexes (PRC) 1 and 2 are intimately involved in progression of many types of cancer including HGSOC. Unlike the consistent constitution of PRC2, PRC1 consists of diverse components whose clinical significance in HGSOC are not entirely clear. Here, prognosis‐associated PRC1 components were identified through data‐mining. CBX2 promoted proliferation and reduced apoptosis of HGSOC cell lines OVCAR4, OVCAR3, and CAOV3. Complete loss of CBX2 by CRISPR‐cas9 editing (CBX2KO) destabilized genome stability with increased spontaneous chromosomal breaks and tendency to polyploidy accompanied by disrupted cell cycle especially stalled G2/M transition and caused severe cell death. Wnt/β‐catenin/LEF1/TCF7L1 was activated in surviving OVCAR4‐CBX2KO clones to bypass the crisis caused by loss of CBX2. The relieve of TCF7L1 core‐promoter region occupied by CBX2 might be one of the possible explanations to TCF7L1 increase in OVCAR4‐CBX2KO clones. Subcutaneous tumor model further validated that depletion of CBX2 repressed HGSOC cell line derived tumor growth. High immunohistochemistry score of CBX2 in primary ovarian cancer tissue associated with advanced clinical stage (p = 0.033), poor overall survival (HR = 3.056, 95% CI: 1.024−9.123), and progression free survival (HR = 4.455, 95% CI: 1.513−13.118) in HGSOC. Overall, our results suggested that CBX2 was a promising prognostic factor and therapeutic target in HGSOC.

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LRH-1 (liver receptor homolog-1) derived affinity peptide ligand to inhibit interactions between β-catenin and LRH-1 in pancreatic cancer cells: from computational design to experimental validation

Cited by 9 publications

References 50 publications

Insect protease inhibitors; promising inhibitory compounds against SARS-CoV-2 main protease

Insect protease inhibitors; promising inhibitory compounds against SARS-CoV-2 main protease

The Medicinal Chemistry and Therapeutic Potential of LRH-1 Modulators

Loss of CBX2 causes genomic instability and Wnt activation in high grade serous ovarian carcinoma cells

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