Biomolecular Modelling & Design Division

Incorporation of Putative Helix-Breaking Amino Acids in the Design of Novel Stapled Peptides: Exploring Biophysical and Cellular Permeability Properties

Published date : 20 Jun 2019

Stapled α-helical peptides represent an emerging superclass of macrocyclic molecules with drug-like properties, including high-affinity target binding, protease resistance, and membrane permeability. As a model system for probing the chemical space available for optimizing these properties, we focused on dual Mdm2/MdmX antagonist stapled peptides related to the p53 N-terminus. Specifically, we first generated a library of ATSP-7041 (Chang et al., 2013) analogs iteratively modified by L-Ala and D-amino acids.

type
Journal Paper
journal
Molecules 2019, Vol. 24, Issue 12, 2292; https://doi.org/10.3390/molecules24122292
Impact Factor
3.060

Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer

Published date : 28 May 2019

An estimated 15–20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2/ERBB2/neu). Two small-molecule tyrosine kinase inhibitors (TKIs), lapatinib and neratinib, have been approved for the treatment of HER2-positive (HER2+) breast cancer.

type
Journal Paper
journal
Cancers 2019, Vol. 11, Issue 6, 37, doi: 10.3390/cancers11060737
Impact Factor
5.326

Exploring Gatekeeper Mutations in EGFR through Computer Simulations

Published date : 17 May 2019

The emergence of resistance against drugs that inhibit a particular protein is a major problem in targeted therapy. There is a clear need for rigorous methods to predict the likelihood of specific drug-resistance mutations arising in response to the binding of a drug. In this work we attempt to develop a robust computational protocol for predicting drug resistant mutations at the gatekeeper position (T790) in EGFR. We explore how mutations at this site affects interactions with ATP and three drugs that are currently used in clinics. We found, as expected,

type
Journal Paper
journal
Journal of Chemical Information and Modeling, 2019, doi: 10.1021/acs.jcim.9b00361
Impact Factor
3.804

AppA: a web server for analysis, comparison, and visualization of contact residues and interfacial waters of antibody–antigen structures and models

Published date : 09 May 2019

The study of contact residues and interfacial waters of antibody–antigen (Ab-Ag) structures could help in understanding the principles of antibody–antigen interactions as well as provide guidance for designing antibodies with improved affinities. Given the rapid pace with which new antibody–antigen structures are deposited in the protein databank (PDB), it is crucial to have computational tools to analyze contact residues and interfacial waters, and investigate them at different levels.

type
Journal Paper
journal
Nuclei Acids Research, 2019, doi: 10.1093/nar/gkz358
Impact Factor
11.561

Efficient development of stable and highly functionalised peptides targeting the CK2a/CK2b protein–protein interaction†

Published date : 12 Apr 2019

The discovery of new Protein–Protein Interaction (PPI) modulators is currently limited by the difficulties associated with the design and synthesis of selective small molecule inhibitors. Peptides are a potential solution for disrupting PPIs; however, they typically suffer from poor stability in vivo and limited tissue penetration hampering their wide spread use as new chemical biology tools and potential therapeutics.

type
Journal Paper
journal
Chemical Science, 2019, 10, 5056-5063, doi: 10.1039/c9sc00798a
Impact Factor
9.063

Allostery in Its Many Disguises: From Theory to Applications

Published date : 01 Apr 2019

Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood.

type
Journal Paper
journal
Structure 27, 2019 Jan 17. pii: S0969-2126(19)30003-6. doi: 10.1016/j.str.2019.01.003
Impact Factor
4.907

Structure mapping of dengue and Zika viruses reveals functional long-range interactions

Published date : 29 Mar 2019

Dengue (DENV) and Zika (ZIKV) viruses are clinically important members of the Flaviviridae family with an 11 kb positive strand RNA genome that folds to enable virus function. Here, we perform structure and interaction mapping on four DENV and ZIKV strains inside virions and in infected cells. Comparative analysis of SHAPE reactivities across serotypes nominates potentially functional regions that are highly structured, conserved, and contain low synonymous mutation rates.

type
Journal Paper
journal
Nature Communications, 2019 Mar 29;10(1):1408. doi: 10.1038/s41467-019-09391-8
Impact Factor
12.353

Inhibition of the NLRP3 inflammasome activation by cell-permeable stapled peptides

Published date : 20 Mar 2019

Interleukin-1β (IL-1β) is a major cytokine that initiates and enhances inflammatory responses. Excessive IL-1β production is a characteristic of most chronic inflammatory diseases, including atherosclerosis, type 2 diabetes, and obesity, which affect a large proportion of the global population. The production of bioactive IL-1β is mediated by a caspase-1-activating complex known as an ‘inflammasome’. The NLRP3 inflammasome has been associated with several human inflammatory and autoimmune diseases and represents a potential therapeutic target for disrupting IL-1β production.

type
Journal Paper
journal
Scientific Reports 9, Article no. 4913 (2019), doi: 10.1038/s41598-019-41211-3
Impact Factor
4.122

"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.

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

An inter-subunit protein-peptide interface that stabilizes the specific activity and oligomerization of the AAA+ chaperone Reptin

Published date : 09 Mar 2019

Reptin is a member of the AAA+ superfamily whose members can exist in equilibrium between monomeric apo forms and ligand bound hexamers. Inter-subunit protein-protein interfaces that stabilize Reptin in its oligomeric state are not well-defined. A self-peptide binding assay identified a protein-peptide interface mapping to an inter-subunit “rim” of the hexamer bridged by Tyrosine-340. A Y340A mutation reduced ADP-dependent oligomer formation using a gel filtration assay, suggesting that Y340 forms a dominant oligomer stabilizing side chain.

type
Journal Paper
journal
Journal of Proteomics, Vol. 199, 2019, Pg 89-101 doi:10.1016/j.jprot.2019.02.012
Impact Factor
3.722