From Angiotensin IV to Small Peptidemimetics Inhibiting Insulin-Regulated Aminopeptidase

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 insulinregulated 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.

Hydrogen Peroxide Induced Toxicity Is Reversed by the Macrocyclic IRAP-Inhibitor HA08 in Primary Hippocampal Cell Cultures

“…These observations stimulated an interest in developing improved IRAP inhibitors, more potent than the short-lived endogenous Ang IV, as a new class of cognitive enhancers and as potential therapeutics for treating a variety of cognitive disorders such as Alzheimer’s disease [ 22 , 23 , 24 ]. A large series of IRAP inhibitors have been reported as well as support for the hypothesis that these types of compounds could serve as suitable starting points for drug discovery projects aimed at developing cognitive enhancers useful in clinic [ 9 , 22 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. A characteristic feature of IRAP is the ability to bind to cyclic substrates [ 33 ].…”

“…One important characteristic of HA08 is its high 2000-fold selectivity for IRAP over AP-N, IRAP; 3.3 nM versus > 7000 nM [ 34 ] and high selectivity versus the homologous enzymes ER aminopeptidase 1 (ERAP 1) and ER aminopeptidase 2 (ERAP 2) [ 36 ]. HA08 has attracted attention as a potential lead structure for more drug-like cognitive enhancers acting via augmenting synaptic plasticity [ 25 , 26 , 29 , 30 , 34 ].…”

Discovery of Selective Nanomolar Inhibitors for Insulin-Regulated Aminopeptidase Based on α-Hydroxy-β-amino Acid Derivatives of Bestatin

“…Still, possible applications of IRAP inhibition in cancer immunotherapy or autoimmunity have been emerging, in particular due to its unique role in cross-presentation by dendritic cells, , an important component of anticancer immune responses . Several chemical scaffolds have been explored as IRAP inhibitors (recently reviewed in ,, ). The first IRAP inhibitors were based on the physiological hexapeptide inhibitor of IRAP angiotensin IV and included linear and macrocyclic analogues. , The first generation of drug-like, small-molecular-weight inhibitors of IRAP were discovered through in silico screening using a homology model of IRAP and included the pyridine derivative HFI-419 and the quinoline derivatives HFI-435 and HFI-437. , In addition, two aryl sulfonamides and a spiro-oxindole dihydroquinazolinone were identified after screening a substance library of 10,500 low-molecular-weight compounds. − Rationally, structure-based designed inhibitors have also been explored, including diaminobenzoic acids and pseudophosphinic peptides. ,, However, despite several years of small-molecule inhibitor development for these enzymes, a clinical application has yet to be reported, suggesting that more drug-like scaffolds need to be explored.…”

Discovery of Selective Inhibitor Leads by Targeting an Allosteric Site in Insulin-Regulated Aminopeptidase

“…Currently, IRAP is under investigation as a pharmaceutical target for cognitive disorders [ 5 ]. Although several IRAP inhibitors have been developed [ 6 , 7 , 8 , 9 ] no clinical applications have yet been reported. Possible reasons include limited selectivity, limited pharmacodynamics or deficient pharmacokinetics.…”