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Review
. 2017 May;284(10):1473-1488.
doi: 10.1111/febs.14009. Epub 2017 Feb 3.

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

Nyssa Drinkwater  1 , Jisook Lee  2 , Wei Yang  1 , Tess R Malcolm  1 , Sheena McGowan  1
Affiliations
Review

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

Nyssa Drinkwater et al. FEBS J. 2017 May.

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.

Keywords: M1 aminopeptidase; anti-cancer; anti-malarial; drug discovery; inhibitors.

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Figures

Figure 1
Figure 1
Structure and conservation of M1 aminopeptidases. (A) X‐ray crystal structure of human aminopeptidase N (APN) 7 colored according to domains with domain I in teal, domain II in orange, domain III in magenta, and domain IV in blue. (B) Crystallographically observed dimer of APN, that is also proposed to occur on the cell surface membrane 7 to which APN is attached via domain I (teal). Domains colored as in A. (C–E) Characteristic structures of M1 aminopeptidases colored according to sequence conservation (high degree of conservation in purple, average in white, and low in cyan). Sequence alignments and conservation calculations performed using ConSurf http://consurf.tau.ac.il/2016/ 83): (C) the M1 aminopeptidase from P. falciparum (PfA‐M1) 27, (D) human endoplasmic reticulum aminopeptidase 1 (ERAP1) 75, (E) human leukotriene A4 hydrolase (LTA4H) 6.
Figure 2
Figure 2
Small‐molecule inhibitors of M1 aminopeptidases that are discussed in the text. (A) Bestatin, a generic aminopeptidase inhibitor. (B) 10o, a PfA‐M1 inhibitor. (C) EC33, an APA inhibitor. (D) ARM1, a selective inhibitor of LTA4H epoxide activity. (E) Bufexamac, a LTA4H inhibitor. (F) DG013A, an inhibitor of ERAP1, ERAP2, and IRAP.
Figure 3
Figure 3
PfA‐M1 in complex with potent inhibitor. The designed inhibitor 10o (purple stick representation), coordinates the catalytic zinc ion (gray sphere) through a hydroxamic acid, and occupies both the S1 and S1′ subsites 32. Key PfA‐M1 active site residues lining the subsites are shown as gray sticks, with those of the zinc‐binding motif colored wheat.
Figure 4
Figure 4
The two distinct catalytic sites of LTA4H. The cocrystal structure of LTA4H in complex with substrate analog OPB‐Pro (purple) and ARM1 (green), a selective inhibitor of the epoxide hydrolase activity 56. Ligands are shown as colored sticks, with dots indicating atomic radii. LTA4H is shown in gray with catalytic zinc (sphere), residues of the zinc‐binding motif (sticks), and solvent‐exposed area (surface representation) indicated.
Figure 5
Figure 5
Bestatin binds APN in a noncanonical pose (orange) 7, rather than the conserved canonical pose for other M1 aminopeptidases (blue, APA in complex with bestatin used as representative 9). APN solvent accessible surface area shown in gray and residues of the zinc‐binding motif as gray sticks. Catalytic zinc ions shown as spheres for APN (orange) and APA (blue).
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