TAN Yaw Sing

"Inhibiting S100B(ββ) for Activating Wild-Type p53: Design of Stapled Peptides"

Published date : 14 Mar 2019

S100B(ββ) is a member of the S100B protein family and is distributed in a cell-specific manner. Its levels are elevated in several cancers such as malignant melanoma and correlate directly with poor prognosis in patients. S100B(ββ) directly interacts with the tumor suppressor p53, inhibiting tetramerization and protein kinase C-dependent phosphorylation, consequently decreasing p53 DNA binding and transcriptional activity, and preventing apoptosis. Thus, S100B(ββ) is being pursued as a target for therapeutic inhibition.

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Journal Paper
journal
ACS Omega 2019, 5, Pg 5335-5344, doi: 10.1021/acsomega.9b00097

Kinetic and thermodynamic effects of phosphorylation on p53 binding to MDM2

Published date : 24 Jan 2019

p53 is frequently mutated in human cancers. Its levels are tightly regulated by the E3 ubiquitin ligase MDM2. The complex between MDM2 and p53 is largely formed by the interaction between the N-terminal domain of MDM2 and the N-terminal transactivation (TA) domain of p53 (residues 15-29). We investigated the kinetic and thermodynamic basis of the MDM2/p53 interaction by using wild-type and mutant variants of the TA domain. We focus on the effects of phosphorylation at positions Thr18 and Ser20 including their substitution with phosphomimetics.

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Journal Paper
journal
Scientific Reports 9, Article no: 693 (2019). doi: 10.1038/s41598-018-36589-5
Impact Factor
4.122

Ultra-High Signal Detection of Human Embryonic Stem Cells Driven by Two-Dimensional Materials

Published date : 08 Aug 2018

We observed a unique bioelectric signal of human embryonic stem cells using direct current−voltage measurements facilitated by few-layered 2DMoS2 sheets. A 1.828 mA cell signal was achieved (2 orders of magnitude higher than previous electrical-based detection methods) as well as multiple cell reading cycles demonstrating I ∼ 1.9 mA. Native stem cell proliferation, viability, and pluripotency were preserved. Molecular dynamics simulations elucidated the origin of the 2D-MoS2 sheet-assisted increase in current flow.

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Journal Paper
journal
ACS Applied Bio Materials, 2018, 1, Pg 210-215, doi: 10.1021/acsabm.8b00085.

Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide

Published date : 05 Jul 2018

Sal-like 4 (SALL4) is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in hepatocellular carcinoma, a malignancy with no effective treatment. In cancer cells, SALL4 associates with nucleosome remodeling deacetylase (NuRD) to silence tumor-suppressor genes, such as PTEN.

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Journal Paper
journal
Proceedings of the National Academy of Sciences of the United States of America (PNAS), July 24, 2018, Vol. 115, no. 30, Pg E7119-E7128, doi: 10.1073/pnas.1801253115
Impact Factor
9.504

Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53

Published date : 19 Dec 2017

Murine double minute 4 protein (MDMX) is crucial for the regulation of the tumor suppressor protein p53. Phosphorylation of the N-terminal domain of MDMX is thought to affect its binding with the transactivation domain of p53, thus playing a role in p53 regulation. In this study, the effects of MDMX phosphorylation on the binding of p53 were investigated using molecular dynamics simulations.

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Journal Paper
journal
Oncotarget, 2017, Vol. 8, No. 68, Pg 112825-112840, doi.org/10.18632/oncotarget.22829
Impact Factor
5.168

An Intramolecular Tryptophan-Condensation Approach for Peptide Stapling

Published date : 08 Dec 2017

Stapled peptides are gaining tremendous interest as next-generation therapeutic agents to target protein-protein interactions. Herein, we report an intramolecular peptide stapling method which links two tryptophan residues at C2 position of the indole moieties via acid-mediated condensation with an aldehyde.

type
Journal Paper
journal
Organic & Biomolecular Chemistry, 2017, doi: 10.1039/C7OB02667F
Impact Factor
3.564

Macrocyclized extended peptides: Inhibiting the substrate-recognition domain of tankyrase

Published date : 13 Jan 2017

We report a double-click macrocyclization approach for the constraint of peptide inhibitors in non-helical or extended conformations. Our targets are the tankyrase proteins (TNKS), poly(ADP-ribose) polymerases that regulate Wnt signaling by targeting Axin for degradation. TNKS are deregulated in many different cancer types, and inhibition of TNKS therefore represents an attractive therapeutic strategy. However, the clinical development of TNKS-specific PARP inhibitors is challenging due to off-target effects and cellular toxicity.

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Journal Paper
journal
Journal of the American Chemical Society, doi: 10.1021/jacs.6b10234
Impact Factor
13.038

Development of Cell-Permeable, Non-Helical, Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer

Published date : 05 Dec 2016

There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA-mediated knockdown of the target protein, HNF1β, in five high- and low-HNF1β-expressing CCC lines.

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Journal Paper
journal
Angewandte Chemie, Vol. 56, Issue 2, Jan 9, 2017 Pg 524-529, doi: 10.1002/anie.201609427
Impact Factor
11.709

Stapled peptide design: principles and roles of computation

Published date : 01 Oct 2016

Stapling is a key technique for stabilising peptides in an α-helical structure. The resultant stapled peptides are then able to compete efficiently for binding to protein targets involved in protein-protein interactions that are mediated by α-helices. Certain general design principles to optimise their binding and biological activity have emerged in recent years. This is accompanied by an increasing use of computational methods in stapled peptide design. In this article, we detail these design principles and review the contributions that computation has made to the field.

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Journal Paper
journal
Drug Discovery Today, Vol. 21, Issue 10, October 2016, Pg 1642-1653, doi: 10.1016/j.drudis.2016.06.012

Functional characterization of p53 pathway components in the ancient metazoan Trichoplax adhaerens

Published date : 28 Sep 2016

The identification of genes encoding a p53 family member and an Mdm2 ortholog in the ancient placozoan Trichoplax adhaerens advocates for the evolutionary conservation of a pivotal stress-response pathway observed in all higher eukaryotes. Here, we recapitulate several key functionalities ascribed to this known interacting protein pair by analysis of the placozoan proteins (Tap53 and TaMdm2) using both in vitro and cellular assays.

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Journal Paper
journal
Scientific Report 6, 33972, 2016, doi:10.1038/srep33972