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Theses
ETUDES PHYSICO-CHIMIQUES DU GLUCAGON-LIKE PEPTIDE ET DE SON RECEPTEUR. OPTIQUE D'UNE NOUVELLE THERAPEUTIQUE POUR LE DIABETE DE TYPE II
Abstract : Glucagon-Like Peptide-1 (GLP-1) represents an excellent candidate molecule for a novel therapeutical approach in the treatment of type II diabetes (NIDDM). Although its mode of action in vivo is well known, some fundamental problems remain to be addressed before GLP-1 might be used, and could substitute the drugs currently used in the treatment of NIDDM.
In particular our understanding of the binding of GLP-1 to its receptor are insufficient and need to be extended by structural studies of both the peptide and its receptor. Moreover, GLP-1 cannot be used in therapy in its native form since it is highly sensitive to degradation by proteases.
In order to define more stable forms of the peptide, several analogs of GLP-1-(7-37) were drawn and synthesized. According to the literature, amino acid positions previously described to play a key role for GLP-1 activity were respected. Amino acid changes were essentially introduced into the amino terminal region. Mutations were also introduced within the central region to corroborate certain hypotheses concerning conformation.
Based on their in vitro binding and activity properties, certain analogs were further analyzed for their biological activity and in vivo stability. In such assays the analog [a8,desR36]GLP-1-(7-37) was found to display a remarkable stability and efficiency, superior to those of wild-type GLP-1-(7-37). Currently, this compound is further developed in pre-clinical trials.
Additionally, the structure of each analogue was performed by biophysical studies (CD and IR-TF), and in view of the in vitro assays results, a potential bio-active structure is proposed.
Finally, in order to gain a better understanding of its interaction(s) with GLP-1, molecular modeling of the receptor was performed. Based on these studies putative interaction sites are proposed. These theoretical considerations were sustained by biophysical analyses and synthesis of fragments of the receptor.
In particular our understanding of the binding of GLP-1 to its receptor are insufficient and need to be extended by structural studies of both the peptide and its receptor. Moreover, GLP-1 cannot be used in therapy in its native form since it is highly sensitive to degradation by proteases.
In order to define more stable forms of the peptide, several analogs of GLP-1-(7-37) were drawn and synthesized. According to the literature, amino acid positions previously described to play a key role for GLP-1 activity were respected. Amino acid changes were essentially introduced into the amino terminal region. Mutations were also introduced within the central region to corroborate certain hypotheses concerning conformation.
Based on their in vitro binding and activity properties, certain analogs were further analyzed for their biological activity and in vivo stability. In such assays the analog [a8,desR36]GLP-1-(7-37) was found to display a remarkable stability and efficiency, superior to those of wild-type GLP-1-(7-37). Currently, this compound is further developed in pre-clinical trials.
Additionally, the structure of each analogue was performed by biophysical studies (CD and IR-TF), and in view of the in vitro assays results, a potential bio-active structure is proposed.
Finally, in order to gain a better understanding of its interaction(s) with GLP-1, molecular modeling of the receptor was performed. Based on these studies putative interaction sites are proposed. These theoretical considerations were sustained by biophysical analyses and synthesis of fragments of the receptor.
Cited literature [176 references]
https://tel.archives-ouvertes.fr/tel-00003484
Contributor : Cyril Sarrauste de Menthière <>
Submitted on : Saturday, October 4, 2003 - 9:33:54 PM
Last modification on : Friday, October 23, 2020 - 4:52:18 PM
Long-term archiving on: : Wednesday, September 12, 2012 - 10:35:31 AM
Contributor : Cyril Sarrauste de Menthière <>
Submitted on : Saturday, October 4, 2003 - 9:33:54 PM
Last modification on : Friday, October 23, 2020 - 4:52:18 PM
Long-term archiving on: : Wednesday, September 12, 2012 - 10:35:31 AM