Aminobenzosuberone Scaffold as a Modular Chemical Tool for the Inhibition of Therapeutically Relevant M1 Aminopeptidases

Emmanuel Salomon,Isabelle Florent,Efstratios Stratikos,Anil Marapaka,Sarah Alavi,Athanasios Stamogiannos,Germain Revelant,Sébastien Albrecht,Céline Schmitt,Anthony Addlagatta,Marjorie Schmitt,Céline Tarnus

doi:10.3390/molecules23102607

Abstract

The synthesis of racemic substituted 7-amino-5,7,8,9-tetrahydrobenzocyclohepten-6-one hydrochlorides was optimized to enhance reproducibility and increase the overall yield. In order to investigate their specificity, series of enzyme inhibition assays were carried out against a diversity of proteases, covering representative members of aspartic, cysteine, metallo and serine endopeptidases and including eight members of the monometallic M1 family of aminopeptidases as well as two members of the bimetallic M17 and M28 aminopeptidase families. This aminobenzosuberone scaffold indeed demonstrated selective inhibition of M1 aminopeptidases to the exclusion of other tested protease families; it was particularly potent against mammalian APN and its bacterial/parasitic orthologues EcPepN and PfAM1.

Highlights

Aminopeptidases (APs) constitute a group of exopeptidases with closely related activities, able to remove amino-acids from unblocked N-termini of peptide and protein substrates
We have closely considered the evaluation of these inhibitors on a number of potential interesting targets within the M1 family of aminopeptidases and established their inhibition profiles
We have reported an improvement of the aminobenzosuberone synthetic route and the biological evaluation of this family of non-peptidic compounds against 6 human and 2 bacterial/parasitic M1 aminopeptidases, plus members of Molecules 2018, 23, x FOR PEER REVIEW

Summary

Introduction

Aminopeptidases (APs) constitute a group of exopeptidases with closely related activities, able to remove amino-acids from unblocked N-termini of peptide and protein substrates. Metallo-APs have been broadly sorted into two important subgroups on the basis of the number of zinc ions in their active site that are involved in catalysis as well as on their protein signatures and folding [1,2] While some of these enzymes contain only one zinc, others possess a binuclear metal centre, usually referred as a co-catalytic. Present mainly as monomers or homo-dimers (in mammals, mainly), metallo-APs occupy various cell compartments and some are secreted, the vast majority operates as membrane bound ectoenzymes or cytosolic catalysts [2,5,6,7] Their evolutionary history indicates that they are related to a complex and ancestral gene family that subsequently yielded series of more divergent sequences [8]. We have a more precise picture of their highly specialized roles depending on their localization with many related paralogous members in mammals

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Discussion

Conclusion