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Título: Solution structure and dynamics of bioactive peptides mimicking NGF
Autores: Beglova, Natalia, 1962-
Fecha: 1999
Publicador: McGill University - MCGILL
Fuente:
Tipo: Electronic Thesis or Dissertation
Tema: Biology, Molecular.
Biology, Neuroscience.
Chemistry, Biochemistry.
Descripción: Nerve growth factor (NGF) belongs to the neurotrophin family of growth factors. NGF can bind to two transmembrane receptors, TrkA and p75. TrkA is the NGF specific tyrosine kinase receptor; p75 is a receptor which is common to all neurotrophins. NGF is required for the development, maintenance and repair of the nervous system. NGF dependent neuronal populations are affected in many diseases and the use of NGF was proposed. Difficulties associated with therapeutic application of proteins and polypeptides could be overcome by the use of small peptidomimetics. Small molecule that can either mimic or inhibit NGF-TrkA signaling could be useful in therapy of a wide range of pathologies from neurodegeneration to cancer.
Peptide mimetics represent an intermediate step towards the development of potent drugs. Small NGF mimetics could be found either in random peptide libraries or by rational drug design. Rational design is based on structure-function knowledge about the binding interface. We approach the problem by designing a series of cyclic peptides from the C-D loop of NGF that is known to interact with TrkA receptor. Nuclear Magnetic Resonace (NMR) was used to determine the structure and dynamics of the peptides in solution. The structural information was combined with bioactivity tests. Comparison of the structures revealed close similarity between the peptides and the conformation of the C-D loop in X-ray crystal structures of NGF. Structural similarity ensures an appropriate backbone conformation and orientation of the sidechains involved in interactions with receptor. This work contributes to our understanding of the structure-function relationships in NGF-TrkA binding. The designed bioactive peptides could serve as a template for further design of smaller peptidomimetics of NGF with improved potency and stability. A similar approach could be used to design functional mimetics of the other neurotrophins.
Idioma: en