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Title of Journal: Amino Acids

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Abbravation: Amino Acids

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Springer Vienna

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DOI

10.1002/bdra.20332

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ISSN

1438-2199

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Positioning of aminopeptidase inhibitors in next g

Authors: Sarina M Hitzerd Sue Ellen Verbrugge Gert Ossenkoppele Gerrit Jansen Godefridus J Peters
Publish Date: 2014/01/03
Volume: 46, Issue: 4, Pages: 793-808
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Abstract

Aminopeptidases represent a class of zinc metalloenzymes that catalyze the cleavage of amino acids nearby the Nterminus of polypeptides resulting in hydrolysis of peptide bonds Aminopeptidases operate downstream of the ubiquitin–proteasome pathway and are implicated in the final step of intracellular protein degradation either by trimming proteasomegenerated peptides for antigen presentation or full hydrolysis into free amino acids for recycling in renewed protein synthesis This review focuses on the function and subcellular location of five key aminopeptidases aminopeptidase N leucine aminopeptidase puromycinsensitive aminopeptidase leukotriene A4 hydrolase and endoplasmic reticulum aminopeptidase 1/2 and their association with different diseases in particular cancer and their current position as target for therapeutic intervention by aminopeptidase inhibitors Historically bestatin was the first prototypical aminopeptidase inhibitor that entered the clinic 35 years ago and is still used for the treatment of lung cancer More recently new generation aminopeptidase inhibitors became available including the aminopeptidase inhibitor prodrug tosedostat which is currently tested in phase II clinical trials for acute myeloid leukemia Beyond bestatin and tosedostat medicinal chemistry has emerged with additional series of potential aminopeptidases inhibitors which are still in an early phase of preclinical investigations The expanded knowledge of the unique mechanism of action of aminopeptidases has revived interest in aminopeptidase inhibitors for drug combination regimens in anticancer treatment In this context this review will discuss relevant features and mechanisms of action of aminopeptidases and will also elaborate on factors contributing to aminopeptidase inhibitor efficacy and/or loss of efficacy due to drug resistancerelated phenomena Together a growing body of data point to aminopeptidase inhibitors as attractive tools for combination chemotherapy hence their implementation may be a step forward in a new era of personalized treatment of cancer patients

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