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dc.contributor.advisorBruno, Stefano-
dc.contributor.authorAlomari, Esra'a Ali Mohammad-
dc.description.abstractProtein therapeutics are proteins used as drugs, purified from natural sources or produced recombinantly – either in the wild-type form or as non-natural mutants. Several potential problems had to be addressed over time to use proteins as therapeutics. In a few cases, the natural source is still the first choice, particularly when the endogenous protein is naturally produced at high concentrations. Serum albumin and several clotting factors, for example, are still purified from human plasma. For proteins that are endogenously produced at low concentrations, the advances in molecular biology proved crucial, allowing the expression of virtually all proteins in host organisms where they are not naturally produced. To obtain high yields in these recombinant systems, host organisms, expression vectors, and fermentation protocols had to be optimized. Another issue associated with protein therapeutics in comparison to small-molecule drugs is their potential instability. Indeed, many factors, such as pH, temperature, solubility, and storage conditions can impact their conformation, which is strictly associated to their bioactivity. Unlike small-molecule drugs, proteins can, therefore, lose their pharmacological activity even if they retain their chemical integrity in terms of primary structure. Therefore, activity needs to be checked at any step of the formulation to make sure that denaturation has not occurred A further issue regarding protein therapeutics is their half-life in vivo. Once proteins have been administered, they can undergo rapid degradation by endogenous proteases or rapid excretion by the kidneys. Protein engineering and chemical modifications have both been used to tackle this potential problem. In my Ph.D. work, I focused on two groups of protein therapeutics for which the aforementioned issues were tackled: 1) Hemoglobin-based oxygen carriers (Part I) are a group of genetically or chemically modified derivatives of hemoglobin used to provide oxygen in various therapeutic applications. Chapter 1 will offer an introduction to the field, focusing on the modulation of their oxygen-binding properties; Chapter 2 will deal with the production of two chemically modified human hemoglobins endowed with different oxygen affinity and their experimentation in a Guinea Pig model; Chapter 3 will focus on engineered fetal hemoglobin derivatives in which both genetic and chemical modifications have been introduced to improve the properties of the product; in chapter 4, the preparation of an acellular perfusion solution for organs is described. 2) Alpha 1-antitrypsin (Part II) is a serpin used as an irreversible inhibitor of trypsin in the treatment of some genetic conditions. For this work, the goal was i) to produce the protein in high yields using a fermentation system; ii) to formulate the protein as powder for nasal application; iii) to improve the half-life of the protein through a chemical modification (PEGylation), and iv) to evaluate protein stability and activity at all steps of the formulation
dc.publisherUniversità degli studi di Parma. Dipartimento di Scienze degli alimenti e del farmacoit
dc.relation.ispartofseriesDottorato di ricerca in Scienze del farmaco, delle biomolecole e dei prodotti per la saluteit
dc.rights© Esra'a Ali Mohammad Alomari, 2020it
dc.subjectHemoglobin-based oxygen carriersit
dc.titleProtein therapeutics for clinical applications: Hemoglobin-based oxygen carriers and modulation of their oxygen-binding propertiesit
dc.typeDoctoral thesisit
Appears in Collections:Scienze del farmaco, delle biolomolecole e dei prodotti per la salute, tesi di dottorato

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