Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures
Shanti Diwakarla, Erik Nylander, Alfhild Gronbladh, Sudarsana Reddy Vanga, Yasmin Shamsudin Khan, Hugo Gutierrez-de-Teran, Jonas Savmarker, Leelee Ng, Pham Vi, Thomas Lundback, Annika Jenmalm-Jensen, Richard Svensson, Per Artursson, Sofia Zelleroth, Karin Engen, Ulrika Rosenstrom, Mats Larhed, Johan Aqvist, Siew Yeen Chai, Mathias Hallberg
ACS Chemical Neuroscience | AMER CHEMICAL SOC | Published : 2016
The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of IRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in h..View full abstract
This work was supported by grants from the Swedish Research Council to the Department of Pharmaceutical Biosciences, the Department of Medicinal Chemistry and the Department of Cell and Molecular Biology, the King Gustaf V and Queen Victoria Freemason Foundation, and the Kjell and Marta Beijer Foundation to the Department of Pharmaceutical Biosciences and to the Department of Medicinal Chemistry at Uppsala University. Siew Yeen Chai was supported by a National Health and Medical Research Council of Australia, Senior Research Fellowship.