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Discovery of α,β‐ and α,γ‐Diamino Acid Scaffolds for the Inhibition of M1 Family Aminopeptidases

The a-amino group is an important moiety in the binding of peptides to their target peptidases. Herein we report that a gamino group displaces the a-amino by adopting an unexpected binding mode, resulting in the inhibition of the peptidase. a,b- and a,g-diamino acids display concentration-dependent inhibition of human cytosolic puromycin-sensitive aminopeptidase (hPSA), porcine microsomal aminopeptidase N (pmAPN), and E. coli aminopeptidase N (ePepN), which are all M1 family aminopeptidases. The X-ray crystal structure of l-a,g-diaminobutyric acid (DABA) in complex with ePepN reveals that the gamino group displaces the a-amino group, which in turn results in a peptide flip at Met 260. Molecular modeling studies suggest that three carbon atoms that are exposed to the S1 pocket in this new mode of binding can be substituted for further development into new leads. M1 class aminopeptidases have a thermolysin-like catalytic domain with the consensus HEXXH-(X)18-E zinc-binding sequence and an exopeptidase motif, GXMEN, in the active site. [1] There are at least nine different members of this family in humans, including the extracellular membrane-associated aminopeptidase N (hAPN, also known as CD13), puromycinsensitive aminopeptidase (hPSA), placental leucine aminopeptidase (P-LAP, also known as oxytocinase), and leukotriene A4 hydrolase (LTA4H). [2] Although each of these enzymes has spe