Supramolecular threading of peptide hydrogel fibrils

There is an increasing demand for biocompatible materials in biomedical applications. Herein, we report a modified α-helical decapeptide segment from the cardiac troponin C, which self-assembles into fibers with a secondary β-sheet structure. These fibers cross-link via a novel supramolecular threading mechanism which results in an atypical stiff hydrogel (G′ ≈ 13 kPa). In this work, we provide a first insight into the understanding of such remarkable cross-linking mechanism, which will aid in the development of new biomaterials with unique properties

Stimuli sensitive polysaccharide based hydrogels as colon targeted drug delivery vehicles : a thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry, Massey University, Turitea campus, Palmerston North, New Zealand

The following journal articles have been removed due to copyright restrictions: Kavianinia, I.; Plieger, P. G.; Kandile, N. G.; Harding, D. R., Fixed-bed column studies on a modified chitosan hydrogel for detoxification of aqueous solutions from copper (II). Carbohydrate Polymers. 2012, 90 (2), 875–886; Kavianinia, I.; Plieger, P. G.; Kandile, N. G.; Harding, D. R., New hydrogels based on symmetrical aromatic anhydrides: Synthesis, characterization and metal ion adsorption evaluation, Carbohydrate Polymers. 2012, 87 (1), 881–893; Kavianinia, I.; Plieger, P. G.; Kandile, N. G.; Harding, D. R., In Vitro Evaluation of Spray-Dried Chitosan Microspheres Crosslinked with Pyromellitic Dianhydride for Oral Colon-Specific Delivery of Protein Drugs. Article first published online: 13 Feb 2013.Administering drugs orally is by far the most widely used route of administration that will help eliminate the pain caused by injection, psychological barriers associated with multiple daily injections and possible infection from injection sites. However, it is important for oral drug administration to overcome several different obstacles during the delivery through the gastrointestinal tract. The barriers can be morphological barriers and physiological factors such as a wide range of pH and enzymatic activities. The lower water content and fluid mobility of the colon, which leads to longer retention times and also lower proteolytic activity of colon compared to other areas of the gastrointestinal tract, make the colon an ideal site for both systemic and local delivery of drugs. Therefore aggressive research efforts have recently focused on development of new strategies for delivering drugs to the colon. As a drug delivery systems, hydrogels have received increasing attention due to their outstanding merits. Among the various hydrogels, including natural, synthetic and natural/synthetic hybrid hydrogels, chitosan has attracted significant attention in a broad range of pharmaceutical and biomedical applications. Chitosan is a hydrophilic polyelectrolyte heteropolysaccharide composed of randomly (1→4)-linked 2- acetamido-2-deoxy-β-D-glucopyranose and 2-amino-2-deoxy-β-D-glucopyranose linked by (1→4)-β-glycosidic bonds. Unlike most known bioadhesive polymers, chitosan displays unique pharmaceutical and biomedical applications due to the large number of hydroxy and amino groups on the backbone of chitosan. These functional groups can be readily modified. This study was commenced with the aim of engineering a carrier with high enough physicochemical stability to reach the colon and to be able to protect a drug from various obstacles throughout the gastrointestinal tract. In this study, a new generation of chitosan derivatives was developed. Furthermore, their viability was investigated for potential applications as drug carriers to the colon. Chitosan based films with improved physical properties from introducing a cyclic imide moiety into the chitosan matrices was developed and characterised. Mechanical, thermal and chemical analyses of these films show that the heterocyclic imide linkage imparts excellent thermal, mechanical and chemical stability to the chitosan film. Additionally, spray dried chitosan microspheres with improved mechanical stability were examined for the controlled drug release of bovine serum albumin as a model protein drug. Additionally, a novel generation of amphoteric crosslinked chitosan derivatives was designed to be pH sensitive and bacterially degradable. Tabletted carriers were designed to protect the drug from the harsh acidic environment of the stomach and the rigorous enzymic activity of the small intestine and deliver the drug to the colon. Tabletted formulation forms of these novel amphoteric derivatives of chitosan showed the excellent potential formulations as colon specific drug delivery vehicles

An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy

The large number of emerging antibody-drug conjugates (ADCs) for cancer therapy has resulted in a significant market ‘boom’, garnering worldwide attention. Despite ADCs presenting huge challenges to researchers, particularly regarding the identification of a suitable combination of antibody, linker, and payload, as of September 2021, 11 ADCs have been granted FDA approval, with eight of these approved since 2017 alone. Optimism for this therapeutic approach is clear, despite the COVID-19 pandemic, 2020 was a landmark year for deals and partnerships in the ADC arena, suggesting that there remains significant interest from Big Pharma. Herein we review the enthusiasm for ADCs by focusing on the features of those approved by the FDA, and offer some thoughts as to where the field is headed

Total Synthesis and Stereochemical Revision of the Anti-Tuberculosis Peptaibol Trichoderin A

The first total synthesis of the postulated structure of the aminolipopeptide trichoderin A and its epimer are reported. A late-stage solution phase <i>C</i>-terminal coupling was employed to introduce the <i>C</i>-terminal aminoalcohol moiety. This methodology provides a foundation to prepare analogues of trichoderin A to establish a structure–activity relationship. NMR spectroscopic analysis established that the C-6 position of the 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (AHMOD) residue in trichoderin A possesses an (<i>R</i>)-configuration as opposed to the originally proposed (<i>S</i>)-configuration

The Anti-Tubercular Aminolipopeptide Trichoderin A Displays Selective Toxicity against Human Pancreatic Ductal Adenocarcinoma Cells Cultured under Glucose Starvation

Pancreatic ductal adenocarcinoma remains a highly debilitating condition with no effective disease-modifying interventions. In our search for natural products with promising anticancer activity, we identified the aminolipopeptide trichoderin A as a potential candidate. While it was initially isolated as an antitubercular peptide, we provide evidence that it is also selectively toxic against BxPC-3 and PANC-1 human pancreatic ductal adenocarcinoma cells cultured under glucose deprivation. This has critical implications for the pancreatic ductal adenocarcinoma, which is characterized by nutrient deprivation due to its hypovascularized network. We have also successfully simplified the trichoderin A peptide backbone, allowing greater accessibility to the peptide for further biological testing. In addition, we also conducted a preliminary investigation into the role of peptide lipidation at the N-terminus. This showed that analogues with longer fatty acyl chains exhibited superior cytotoxicity than those with shorter acyl chains. Further structural optimization of trichoderin A is anticipated to improve its biological activity, whilst ongoing mechanistic studies to elucidate its intracellular mechanism of action are conducted in parallel

Total Synthesis of the Highly <i>N-</i>Methylated Acetylene-Containing Anticancer Peptide Jahanyne

The first total synthesis of the highly <i>N-</i>methylated acetylene-containing lipopeptide jahanyne, an apoptosis-inducing natural product from marine cyanobacteria, is reported. A late-stage solution-phase coupling enabled introduction of the <i>C</i>-terminal ketone pyrrolidine moiety. A modified Fmoc solid-phase synthesis strategy was adopted to effectively couple multiple sterically hindered <i>N</i>-methylated amino acids while suppressing epimerization. The total synthesis has enabled confirmation of the proposed absolute configuration of natural jahanyne

On-Resin Conjugation of the Ruthenium Anticancer Agent Plecstatin‑1 to Peptide Vectors

Ruthenium piano-stool complexes have been explored for their anticancer activity and some promising compounds have been reported. Herein, we conjugated a derivative of plecstatin-1 to peptides in order to increase their cancer cell targeting ability. For this purpose, plecstatin-1 was modified at the arene ligand to introduce a functional amine handle (3), which resulted in a compound that showed similar activity in an in vitro anticancer activity assay. The cell-penetrating peptide TAT48–60, tumor-targeting neurotensin8–13, and plectin-targeting peptide were functionalized with succinyl or β-Ala-succinyl linkers under standard solid-phase peptide synthesis (SPPS) conditions to spatially separate the peptide backbones from the bioactive metal complexes. These modifications allowed for conjugating precursor 3 to the peptides on resin yielding the desired metal-peptide conjugates (MPCs), as confirmed by high-performance liquid chromatography (HPLC), NMR spectroscopy, and mass spectrometry (MS). The MPCs were studied for their behavior in aqueous solution and under acidic conditions and resembled that of the parent compound plecstatin-1. In in vitro anticancer activity studies in a small panel of cancer cell lines, the TAT-based MPCs showed the highest activity, while the other MPCs were virtually inactive. However, the MPCs were significantly less active than the small molecules plecstatin-1 and 3, which can be explained by the reduced cell uptake as determined by inductively coupled plasma MS (ICP-MS). Although the MPCs did not display potent anticancer activities, the developed conjugation strategy can be extended toward other metal complexes, which may be able to utilize the targeting properties of peptides