Cyclic peptides are investigated as a platform to induce different orientations between various ligands. Through click chemistry, a variety of Toll-like receptor ligands can be attached to the... Show moreCyclic peptides are investigated as a platform to induce different orientations between various ligands. Through click chemistry, a variety of Toll-like receptor ligands can be attached to the cyclic peptides, which are based on gramicidin S. Show less
Alzheimer's disease is manifested in amyloid fibril but caused by protofibril oligomers of A_ peptide and tau protein. I discovered a molecular mechanism which involves a new globular state of the... Show moreAlzheimer's disease is manifested in amyloid fibril but caused by protofibril oligomers of A_ peptide and tau protein. I discovered a molecular mechanism which involves a new globular state of the A_ peptide formed by protofibril oligomers, and from which fibrils can nucleate. Another striking finding in my thesis is to present new concept to inhibit amyloid fibrillation. For instance, natural factors found in vivo, such as ,lysozyme, insulin and spermine, and non-natural factors found in vitro, like gramicidin S, can interfere with the toxicity and fibrillation of A_. Show less
The research described in this thesis focuses on synthetic modifications of the antibiotic peptide gramicidin S (GS). The aim of the research is the development of non__toxic analogs of GS using... Show moreThe research described in this thesis focuses on synthetic modifications of the antibiotic peptide gramicidin S (GS). The aim of the research is the development of non__toxic analogs of GS using conformational and amphipathic changes induced by sugar amino acids (SAAs) and/or non__proteinogenic amino acids. The physical properties of the synthetic derivatives were studied using NMR, Molecular Modeling, Circular Dichroism, LC/MS, and X-ray techniques. Evaluation of the biological activity (antimicrobial activity and toxicity) of the peptides revealed that various synthetic derivatives appeared to be less toxic than GS. By the frequent use and misuse of antibiotics the amount of untreatable bacterial infections has increased. This research has contributed to the development of antibiotics for which resistance by bacteria should not easily occur. Show less
The effect of the incorporation of alpha- and beta-amino acids in model peptide gramicidin S is described. Several techniques were applied, such as NMR and X-ray crystallography. In addition the... Show moreThe effect of the incorporation of alpha- and beta-amino acids in model peptide gramicidin S is described. Several techniques were applied, such as NMR and X-ray crystallography. In addition the activity of the newly obtained peptides towards bacterial and mammalian cell membranes was investigated. Show less
This Thesis deals with the design, synthesis and biological evaluation of peptide-based drugs. In chapters 1-4, the development of peptides derived from natural gluten which can serve as drugs to... Show moreThis Thesis deals with the design, synthesis and biological evaluation of peptide-based drugs. In chapters 1-4, the development of peptides derived from natural gluten which can serve as drugs to combat the symptoms of celiac disease is described. These symptoms are caused by a misdirected immune response towards dietary gluten in genetically predisposed individuals. Peptides which can inhibit this immune response possibly can be used as an addition to the gluten-free diet, which is the only therapy available today. In Chapters 5 and 6, the synthesis and biological evaluation analogs of the antibiotic peptide Gramicidin S is described. Gramicidin S is a naturally occurring antibiotic peptide. It is very effective against bacteria, but also exhibits toxicity towards human red blood cells which limits its use to topical applications. Analogs of this natural peptide may lead to efficient antibiotics which are broadly applicable. Show less
The last decade has witnessed an increased occurrence of bacterial resistance against antibiotics. The first part of this thesis describes the discovery of a novel target, protein kinase B / Akt1,... Show moreThe last decade has witnessed an increased occurrence of bacterial resistance against antibiotics. The first part of this thesis describes the discovery of a novel target, protein kinase B / Akt1, that may be used to combat infection with pathogenic bacteria like Salmonella typhimurium. Inhibitors of this enzyme are currently being developed as anti-tumor agents. These molecules can now also be seen as potential antibiotics. The synthesis and biological evaluation of several series of new inhibitors of this enzyme are described. This resulted in the identification of a compound with sufficient potency and selectivity to allow in vivo inhibition of Salmonella outgrowth. The second part describes the optimization of an existing antibiotic, Gramicidin S. This is a naturally occurring decapeptide that disrupts the cellular membrane of bacteria. This results in leakage of intracellular contents and bacterial death. Unfortunately, Gramicidin S is toxic for red blood cells since their membrane is also destroyed. As part of an ongoing project to reduce the toxicity against red blood cells, part of the original decapeptide is replaced by synthetic molecules. One compound showed similar activity against bacteria and reduced toxicity against red blood cells. Further research is needed to further improve this antibiotic. Show less
