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Peptides to peptidomimetics
Secondary structure mimetics
- Status
- Established Project
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- Background
- Drug design would benefit greatly from knowledge of the biologically active conformation of peptides. Since small linear peptides possess considerable conformational flexibility and biophysical studies of peptides in their natural environment is still in its infancy, the biologically active conformation has to be approached in a different way. The study of conformationally restricted analogues seems to be a worthwhile alternative.
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- Aim
- To transform peptides into non-peptidic analogues by the iterative incorporation of well defined secondary structure mimetics in target peptides which recognize receptors of unknown 3D structure.
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- Method
- Our strategy comprises, in an iterative process: a) rigidification of the peptide and pharmacological evaluation, b) generation of a hypothesis of the bioactive conformation of the rigidified peptide by use of conformational analyses studies, c) incorporation of secondary structure mimetics and evaluation, d) elimination of non-essential molecular fragments followed by optimization including, if relevant, structure optimization based on combinatorial chemistry to provide low molecular weight compounds. We aim to explore the potential of this strategy for the development of drugs acting at peptide receptors. This strategy, or modifications thereof, we believe should have a high generality and be applicable to numerous peptides particularly in cases where the bioactive conformation comprises a well defined secondary structure motif. The octapeptide angiotensin II is primary target suitable as a model peptide in the development and fine-tuning of the design strategy.
Angiotensin II receptor type 4 ligands
- Status
- New Project
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- Indication
- Not known
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- Background
- The octapeptide angiotensin II is known as a potent effector of the renin-angiotensin system and the development of highly selective receptor ligands for this peptide has allowed the identification of several angiotensin II receptor subtypes; AT1, AT2, AT3 and AT4. Most of the known effects of angiotensin II can be attributed to the AT1 receptor (i.e. vasoconstriction). The relevance of the AT4 receptor is poorly understood and data regarding its properties mainly emerge from binding studies. The observed distribution of AT4 sites for angiotensin IV (the 3-8 fragment of ang II) indicated that this receptor is present throughout several neuronal systems and most striking is its location in motor nuclei and motor associated neurons. Most of the physiology of the AT4 receptor system, that is known up to present, relates principally to cerebral vascular function and growth control of vascular tissues.
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- AimTo design and synthesize selective AT4 receptor ligands and to characterize their mediation of CNS effects.
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- Method
- Systematic cyclization and bicyclization of angiotensin IV followed by iterative incorporation of secondary structure mimetics as described in the project "Secondary structure mimetics." Small biased libraries of cyclised pseudopeptides are constructed in order to obtain information on the bioactive conformation of angiotensin IV and for the guidance of further design.
Angiotensin II receptor type 2 agonists
- Status
- Established Project
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- Indication
- Heart failure, sodium bicarbonate secretion
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- Background
- The role of the AT2 receptor is not jet fully understood. It has been suggested that the AT2 receptor is involved in renal function, growth, restinosis, wound healing cerebral blood flow control and control of bicarbonate secretion. While both selective and non-selective nonpeptidic AT1 receptor agonists recently have been developed no examples of selective nonpeptidic AT2 agonists have been disclosed. Access to a selective AT2 agonist should constitute an important research tool in the effort to clarify the role of the AT2 receptor.
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- Aim
- To design and synthesize selective nonpeptidic AT2 receptor agonists.
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- Method
- We have established relevant AT1 and AT2 receptor assays that allow fast and efficient screening. A nonselective AT1/AT2 receptor agonist is used as starting point. Our strategy involves systematic modifications of nonselective agonists and in addition the application of the concept presented in the "secondary structure mimetics" project.
SP1-7 ligands
- Status
- New Project
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- Indication
- Opioid abstinence, pain
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- Background
- The undecapeptide substance P (SP) is involved in pain transmission in the CNS. Its heptapeptidic degradation product SP1-7 has been shown to oppose the nociceptive effect of SP and to modulate several other actions of SP. No specific receptor for SP1-7 has yet been cloned. However, a specific binding site for SP1-7 in the rat spinal cord has been identified. In a screening of various neuropeptides the tetrapeptide µ-receptor agonist endomorphin-2 (EM-2) was found to efficiently interact with this binding site. Thus, EM-2 is a promising lead for further development of less-peptidic SP1-7 mimetics.
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- Aim
- To design and synthesize stable and drug-like neuropeptide mimetics of substance P1-7 (SP1-7, H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) and endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2) to be used as tools for the identification of the SP1-7 receptor and to characterize their mediation of CNS effects.
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- Method
- Informative structure-activity relationship (SAR) for SP1-7 and EM-2 will be achieved by Ala-scans and truncation studies. Based on the obtained SAR an iterative process involving preparation of rigidified pseudopeptides and incorporation of secondary structure mimics will be performed according to the method described in the project "Secondary structure mimetics". Affinity data of the synthesized ligands will give information on the bioactive conformation of SP1-7 ligands that will guide further design of peptidomimetics.
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Last modified at 2008-08-12 10:50 by Sorin Srbu
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