Molnar, Anca Florina (2009) Development of Innovative Vaccine and/or Antibacterial Molecules Applied to Haemophilus Influenzae Porins. [Tesi di dottorato] (Unpublished)

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The present thesis has as its objective the design and development of new peptide and peptidomimetic molecules able to functioning as new vaccines or new antibiotics more effective and/or lower cost than currently available, against the meningitis. P2 porin from the bacterium Haemophilus influenzae has been chosen as subject of the present thesis, both thanks to the previous experience and expertise on this system and in all the required technologies in the groups where the experimental work has been done, and because of the high practical interest for the development of potential vaccines or antibiotics against meningitis caused by Hib. On the basis of the just mentioned previous results a critical step is the identification of a possible bioactive conformation for loop L7 of P2 porin. In this view, my research activity has been addressed to: a) widen and complete the bioinformatic search for loops similar to L7 b) develop a program, written in the Python programming language, for compared conformational analysis of loops, aimed at identifying structural similarities and at clustering conformations into structural families, starting from subsequences identified in pattern searches on protein sequences whose three-dimensional structures are deposited into the Protein Data Bank (PDB) repository. c) the design of two series of cyclic peptides that stabilize the structure of loop L7 d) the molecular dynamics simulations of designed peptides, to check their conformational stability and similarity with the corresponding starting conformations e) the implementation of a protocol for a “bioinformatic check” of designed peptides, based on the “assembly” of designed peptides on the new P2 porin models. f) the synthesis of those peptides that are considered the best in terms of overall conformational stability and compatibility with the model of P2 porin. g) the biological test of synthesized peptides for an evaluation of their ability to mimic the biological activity of loop L7 The use of peptides and / or peptidomimetics as principals classes of molecules for use in the project is contemplated both, the study phase, because of their versatility and ease of synthesis, and to that applied for the opportunity to realize large-scale production with biotechnological techniques.

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