Nanomaterials and methods for cancer therapy: 2D materials, biomolecules, and molecular dynamics simulations.

This review explores the potential of biomolecule-based nanomaterials, , protein, peptide, nucleic acid, and polysaccharide-based nanomaterials, in cancer nanomedicine. It highlights the wide range of design possibilities for creating multifunctional nanomedicines using these biomolecule-based nanomaterials. This review also analyzes the primary obstacles in cancer nanomedicine that can be resolved through the usage of nanomaterials based on biomolecules.

HNF4A and HNF1A exhibit tissue specific target gene regulation in pancreatic beta cells and hepatocytes.

HNF4A and HNF1A encode transcription factors that are important for the development and function of the pancreas and liver. Mutations in both genes have been directly linked to Maturity Onset Diabetes of the Young (MODY) and type 2 diabetes (T2D) risk. To better define the pleiotropic gene regulatory roles of HNF4A and HNF1A, we generated a comprehensive genome-wide map of their binding targets in pancreatic and hepatic cells using ChIP-Seq.

Dissecting the geometric and hydrophobic constraints of stapled peptides.

Stapled peptides are a promising class of molecules with potential as highly specific probes of protein-protein interactions and as therapeutics. Hydrocarbon stapling affects the peptide properties through the interplay of two factors: enhancing the overall hydrophobicity and constraining the conformational flexibility. By constructing a series of virtual peptides, we study the role of each factor in modulating the structural properties of a hydrocarbon-stapled peptide PM2, which has been shown to enter cells, engage its target Mouse Double Minute 2 (MDM2), and activate p53.

Development of stapled NONO-associated peptides reveals unexpected cell permeability and nuclear localisation.

The non-POU domain-containing octamer-binding protein (NONO) is a nucleic acid-binding protein with diverse functions that has been identified as a potential cancer target in cell biology studies. Little is known about structural motifs that mediate binding to NONO apart from its ability to form homodimers, as well as heterodimers and oligomers with related homologues. We report a stapling approach to macrocyclise helical peptides derived from the insulin-like growth factor binding protein (IGFBP-3) that NONO interacts with, and also from the dimerisation domain of NONO itself.

Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription.

Regulation of global transcription output is important for normal development and disease, but little is known about the mechanisms involved. DNA topoisomerase I (TOP1) is an enzyme well-known for its role in relieving DNA supercoils for enabling transcription. Here, we report a non-enzymatic function of TOP1 that downregulates RNA synthesis.

Shape complementarity processes for ultrashort-burst sensitive M13-PEG-WS-powered MCF-7 cancer cell sensors.

Biomarkers have the potential to be utilized in disease diagnosis, prediction and monitoring. The cancer cell type is a leading candidate for next-generation biomarkers. Although traditional digital biomolecular sensor (DBS) technology has shown to be effective in assessing cell-based interactions, low cell-population detection of cancer cell types is extremely challenging.

An Efficient, Short Stimulus PANC-1 Cancer Cell Ablation and Electrothermal Therapy Driven by Hydrophobic Interactions.

Promising results in clinical studies have been demonstrated by the utilization of electrothermal agents (ETAs) in cancer therapy. However, a difficulty arises from the balance between facilitating the degradation of ETAs, and at the same time, increasing the electrothermal performance/stability required for highly efficient treatment. In this study, we controlled the thermal signature of the MoS by harnessing MoS nanostructures with M13 phage (MNM) via the structural assembling (hydrophobic interaction) phenomena and developed a combined PANC-1 cancer cell-MNM alternating current (AC)-stimulus framework for cancer cell ablation and electrothermal therapy.

Success probability of high-affinity DNA aptamer generation by genetic alphabet expansion.

Nucleic acid aptamers as antibody alternatives bind specifically to target molecules. These aptamers are generated by isolating candidates from libraries with random sequence fragments, through an evolutionary engineering system. We recently reported a high-affinity DNA aptamer generation method that introduces unnatural bases (UBs) as a fifth letter into the library, by genetic alphabet expansion.

Ultrasensitive two-dimensional material-based MCF-7 cancer cell sensor driven by perturbation processes.

Changes in lipid composition and structure during cell development can be markers for cell apoptosis or various diseases such as cancer. Although traditional fluorescence techniques utilising molecular probes have been studied, these methods are limited in studying these micro-changes as they require complex probe preparation and cannot be reused, making cell monitoring and detection challenging. Here, we developed a direct current (DC) resistance sensor based on two-dimensional (2D) molybdenum disulfide (MoS) nanosheets to enable cancer cell-specific detection dependent on micro-changes in the cancer cell membrane.

Ultrasensitive Detection of MCF-7 Cells with a Carbon Nanotube-Based Optoelectronic-Pulse Sensor Framework.

Biosensors are of vital significance for healthcare by supporting the management of infectious diseases for preventing pandemics and the diagnosis of life-threatening conditions such as cancer. However, the advancement of the field can be limited by low sensing accuracy. Here, we altered the bioelectrical signatures of the cells using carbon nanotubes (CNTs) via structural loosening effects.

Accelerated Ligand-Mapping Molecular Dynamics Simulations for the Detection of Recalcitrant Cryptic Pockets and Occluded Binding Sites.

The identification and characterization of binding sites is a critical component of structure-based drug design (SBDD). Probe-based/cosolvent molecular dynamics (MD) methods that allow for protein flexibility have been developed to predict ligand binding sites. However, cryptic pockets that appear only upon ligand binding and occluded binding sites with no access to the solvent pose significant challenges to these methods.

Progressive endoplasmic reticulum stress over time due to human insulin gene mutation contributes to pancreatic beta cell dysfunction.

Aims/hypothesis: We studied the effects of heterozygous human INS gene mutations on insulin secretion, endoplasmic reticulum (ER) stress and other mechanisms in both MIN6 and human induced pluripotent stem cells (hiPSC)-derived beta-like cells, as well as the effects of prolonged overexpression of mutant human INS in MIN6 cells.

Methods: We modelled the structure of mutant C109Y and G32V proinsulin computationally to examine the in silico effects. We then overexpressed either wild-type (WT), mutant (C109Y or G32V), or both WT and mutant human preproinsulin in MIN6 cells, both transiently and stably over several weeks.

The nanotube express: Delivering a stapled peptide to the cell surface.

Hypothesis: Carbon nanotubes (CNTs) represent a novel platform for cellular delivery of therapeutic peptides. Chemically-functionalized CNTs may enhance peptide uptake by improving their membrane targeting properties.

Experiments: Using coarse-grained (CG) molecular dynamics (MD) simulations, we investigate membrane interactions of a peptide conjugated to pristine and chemically-modified CNTs.

Cyclisation strategies for stabilising peptides with irregular conformations.

Cyclisation is a common synthetic strategy for enhancing the therapeutic potential of peptide-based molecules. While there are extensive studies on peptide cyclisation for reinforcing regular secondary structures such as α-helices and β-sheets, there are remarkably few reports of cyclising peptides which adopt irregular conformations in their bioactive target-bound state. In this review, we highlight examples where cyclisation techniques have been successful in stabilising irregular conformations, then discuss how the design of cyclic constraints for irregularly structured peptides can be informed by existing β-strand stabilisation approaches, new computational design techniques, and structural principles extracted from cyclic peptide library screening hits.

Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells.

Heterozygous HNF1A gene mutations can cause maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. However, specific mechanisms of MODY3 in humans remain unclear due to lack of access to diseased human pancreatic cells. Here, we utilize MODY3 patient-derived human induced pluripotent stem cells (hiPSCs) to study the effect(s) of a causal HNF1A mutation on pancreatic function.

Macrocyclization of an all-d linear α-helical peptide imparts cellular permeability.

Peptide-based molecules hold great potential as targeted inhibitors of intracellular protein-protein interactions (PPIs). Indeed, the vast diversity of chemical space conferred through their primary, secondary and tertiary structures allows these molecules to be applied to targets that are typically deemed intractable small molecules. However, the development of peptide therapeutics has been hindered by their limited conformational stability, proteolytic sensitivity and cell permeability.

Straightforward Incorporation of Multiple Ligand Types into Molecular Dynamics Simulations for Efficient Binding Site Detection and Characterization.

Binding site identification and characterization is an important initial step in structure-based drug design. To account for the effects of protein flexibility and solvation, several cosolvent molecular dynamics (MD) simulation methods that incorporate small organic molecules into the protein's solvent box to probe for binding sites have been developed. However, most of these methods are highly inefficient, as they allow for the use of only one probe type at a time, which means that multiple sets of simulations have to be performed to map different types of binding sites.

Synthesis of Chiral Alkenyl Cyclopropane Amino Acids for Incorporation into Stapled Peptides.

α,α'-Disubstituted amino acids serve as important non-proteinogenic amino acids in the construction of stabilized helical peptides. To expand the repertoire of α,α'-disubstituted amino acids, chiral alkenyl-containing cyclopropane amino acids were synthesized via a two-step olefination and cyclopropanation procedure. Herein, we report the first example of the use of alkenyl cyclopropane building blocks to constrain MDM2-targeting helical peptides.

Stereoisomerism of stapled peptide inhibitors of the p53-Mdm2 interaction: an assessment of synthetic strategies and activity profiles.

All-hydrocarbon, , stapled peptide inhibitors of the p53-Mdm2 interaction have emerged as promising new leads for cancer therapy. Typical chemical synthesis olefin metathesis results in the formation of both - and -isomers, an observation that is rarely disclosed but may be of importance in targeting PPI. In this study, we evaluated the effect of staple geometry on the biological activity of five p53-reactivating peptides.

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

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.

Targeted covalent inhibitors of MDM2 using electrophile-bearing stapled peptides.

Herein, we describe the development of a novel staple with an electrophilic warhead to enable the generation of stapled peptide covalent inhibitors of the p53-MDM2 protein-protein interaction (PPI). The peptide developed showed complete and selective covalent binding resulting in potent inhibition of p53-MDM2 PPI.

Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein-protein interaction.

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 and limited tissue penetration hampering their wide spread use as new chemical biology tools and potential therapeutics. In this work, a combination of CuAAC chemistry, molecular modelling, X-ray crystallography, and biological validation allowed us to develop highly functionalised peptide PPI inhibitors of the protein CK2.