Abstract
It was reported three decades ago that intracerebroventricular injection of angiotensin IV (Ang IV, Val-Tyr-Ile-His-Pro-Phe) improved memory and learning in the rat. There are several explanations for these positive effects of the hexapeptide and related analogues on cognition available in the literature. In 2001, it was proposed that the insulin-regulated aminopeptidase (IRAP) is a main target for Ang IV and that Ang IV serves as an inhibitor of the enzyme. The focus of this review is the efforts to stepwise transform the hexapeptide into more drug-like Ang IV peptidemimetics serving as IRAP inhibitors. Moreover, the discovery of IRAP inhibitors by virtual and substance library screening and direct design applying knowledge of the structure of IRAP and of related enzymes is briefly presented.
Highlights
Angiotensin IV (Ang IV) is a small bioactive peptide in the renin-angiotensin system (RAS) formed after proteolytic degradation of angiotensin II (Ang II)
The encouraging data obtained after administration of Ang IV in the experimental models and the impact of Ang IV on parameters anticipated to be linked to cognition promoted an interest in more detailed studies of the hexapeptide
A series linear Ang IV analogues demonstrating improved metabolic stability and very high affinity to insulinregulated aminopeptidase (IRAP) have been reported, e.g., the potent hexapeptides (AL-11) and (IVDE77) with Ki values of 7.6 and 1.7 nM, respectively, data to be compared with the Ki value of Ang IV of 62 nM in the same binding assay
Summary
Angiotensin IV (Ang IV) is a small bioactive peptide in the renin-angiotensin system (RAS) formed after proteolytic degradation of angiotensin II (Ang II). After systematic structure activity studies (SAR) of Ang IV analogues, involving glycine and D-amino acid scans in combination with displacement and incorporation of various alternative amino acid residues it became clear that the N-terminal Val-Tyr-Ile residues of the peptide ligands were important for high affinity to the specific binding site identified (Sardinia et al, 1993), named the AT4 receptor
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