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Cyclic insulin-regu...
Cyclic insulin-regulated aminopeptidase (IRAP)/AT(4) receptor ligands
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- Axén, Andreas (författare)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Lindeberg, Gunnar (författare)
- Uppsala universitet,Institutionen för läkemedelskemi
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Demaegdt, Heidi (författare)
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Vauquelin, Georges (författare)
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- Karlén, Anders (författare)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Hallberg, Mathias (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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(creator_code:org_t)
- 2006
- 2006
- Engelska.
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 12:11, s. 705-713
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- The angiotensin IV receptor (AT(4) receptor) is the insulin-regulated aminopeptidase enzyme (IRAP, EC 3.4.11.3). This membrane-spanning enzyme belongs to the M1 family of zinc-dependent metallo-peptidases. It has been proposed that AT4 receptor ligands exert their physiological effects by binding to the active site of IRAP and thereby inhibiting the catalytic activity of the enzyme. The biological activity of a large series of linear angiotensin IV analogs was previously disclosed. Herein, the synthesis and biological evaluation of a series of angiotensin IV analogs, encompassing macrocyclic ring systems of different sizes, are presented. It is demonstrated that disulfide cyclizations of angiotensin IV can deliver ligands with high IRAP/AT4 receptor affinity. One ligand, with an 11-membered ring system (4), inhibited human IRAP and aminopeptidase N (AP-N) activity with similar potency as angiotensin IV but was considerably more stable than angiotensin IV toward enzymatic degradation. The compound provides a promising starting point for further optimization toward more drug-like derivatives. The cyclic constrained analogs allowed us to propose a tentative bioactive conformation of angiotensin IV and it seems that the peptide adopts an inverse gamma-turn at the C-terminal.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- angiotensin IV
- insulin-regulated aminopeptidase
- IRAP
- cystinyl aminopeptidase
- aminopeptidase N
- disulfide cyclization
- structure -activity relationship
- peptide synthesis
- bioactive conformation
- PHARMACY
- FARMACI
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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