M1 aminopeptidases as drug targets: broad applications or therapeutic niche?

Abstract

M1 aminopeptidase enzymes are a diverse family of metalloenzymes characterized by conserved structure and reaction specificity. Excluding viruses, M1 aminopeptidases are distributed throughout all phyla, and have been implicated in a wide range of functions including cell maintenance, growth and development, and defense. The structure and catalytic mechanism of M1 aminopeptidases are well understood, and make them ideal candidates for the design of small-molecule inhibitors. As a result, many research groups have assessed their utility as therapeutic targets for both infectious and chronic diseases of humans, and many inhibitors with a range of target specificities and potential therapeutic applications have been developed. Herein, we have aimed to address these studies, to determine whether the family of M1 aminopeptidases does in fact present a universal target for the treatment of a diverse range of human diseases. Our analysis indicates that early validation of M1 aminopeptidases as therapeutic targets is often overlooked, which prevents the enzymes from being confirmed as drug targets. This validation cannot be neglected, and needs to include a thorough characterization of enzymes' specific roles within complex physiological pathways. Furthermore, any chemical probes used in target validation must be carefully designed to ensure that specificity over the closely related enzymes has been achieved. While many drug discovery programs that target M1 aminopeptidases remain in their infancy, certain inhibitors have shown promise for the treatment of a range of conditions including malaria, hypertension, and cancer.

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…Methionine aminopeptidases (MetAPs), sometimes referred to as M1‐aminopeptidases, are a diverse family of evolutionarily conserved metalloenzymes, which catalyse the post‐translational removal of the initiator N‐terminal methionine residue during protein biosynthesis. This essential process has led to MetAPs being proposed as potential targets for both chronic and infectious disease . Prokaryotes generally only generate type 1 MetAP (MetAP‐1), which can be subdivided into types 1a–d, whereas eukaryotes encode an additional enzyme, MetAP‐2, which differs by an insert of 60 amino acids .…”

“…point out that an organism′s ability to generate multiple subtypes of MetAPs necessitates robust target validation studies when targeting a specific member of this family. This has often been neglected, leading to unreliable claims of antimicrobial activity . The active site of all MetAPs coordinate two adjacent metal cations through identical metal‐binding regions .…”

Mapping the Pathway and Dynamics of Bestatin Inhibition of the Plasmodium falciparum M1 Aminopeptidase PfA‐M1

“…Excluding viruses, M1 aminopeptidases are distributed throughout all phyla, and have been implicated in a wide range of functions including cell maintenance, growth and development, and defense . The catalytic domain and active sites of the M1 aminopeptidases share the highest percent sequence identity within the superfamily and includes conservation of key residues involved in the proteolytic mechanism .…”

“…Excluding viruses, M1 aminopeptidases are distributed throughout all phyla, and have been implicated in a wide range of functions including cell maintenance, growth and development, and defense . The catalytic domain and active sites of the M1 aminopeptidases share the highest percent sequence identity within the superfamily and includes conservation of key residues involved in the proteolytic mechanism . Understanding the dynamics of the active site and S1/S1′ substrate pockets may provide new avenues to selectivity and potency of inhibitors, not only for our team looking to produce antimalarials, but also for inhibitors of the human cancer target, aminopeptidase N (APN) …”

Discovery of novel non-competitive inhibitors of mammalian neutral M1 aminopeptidase (APN)

“…A natural APN inhibitor, bestatin, is a substrate analog for APN and demonstrates antitumor activities [12]. However, it should be noted that these generic inhibitors often show activity against other aminopeptidase families [13].…”