From Angiotensin IV to Small Peptidemimetics Inhibiting Insulin-Regulated Aminopeptidase

Mathias Hallberg; Mats Larhed

doi:10.3389/fphar.2020.590855

From Angiotensin IV to Small Peptidemimetics Inhibiting Insulin-Regulated Aminopeptidase

Front Pharmacol. 2020 Oct 15:11:590855. doi: 10.3389/fphar.2020.590855. eCollection 2020.

Authors

Mathias Hallberg¹, Mats Larhed²

Affiliations

¹ The Beijer Laboratory, Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, BMC, Uppsala University, Uppsala, Sweden.
² Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Uppsala, Sweden.

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.

Keywords: aminopeptidase N; angiotensin IV; cystinyl aminopeptidase; insulin-regulated aminopeptidase; peptidemimetics.

Publication types

Review