A structural insight into the P1S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases.
N'-substituted 1,2-diaminoethylphosphonic acids and 1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of the unexpected selectivity of these inhibitors of M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic acids were obtained via aziridines in an improved synthetic procedure that was further expanded for the phosphinic pseudodipeptide system. The inhibitory activity, measured for three M1 and one M17 metalloaminopeptidases of different sources (bacterial, human and porcine), revealed several potent compounds (e.g., Ki = 65 nM of 1u for HsAPN). Two structures of an M1 representative (APN from Neisseria meningitidis) in complex with N-benzyl-1,2-diaminoethylphosphonic acid and N-cyclohexyl-1,2-diaminoethylphosphonic acid were determined by the X-ray crystallography. The analysis of these structures and the models of the phosphonic acid complexes of the human ortholog provided an insight into the role of the additional amino group and the hydrophobic substituents of the ligands within the S1 active site region.
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
Ewelina
E
Węglarz-Tomczak
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
Łukasz
Ł
Berlicki
Institute of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland.
Małgorzata
M
Pawełczak
Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, USA.
Bogusław
B
Nocek
Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, USA.
Andrzej
A
Joachimiak
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland. Electronic address: artur.mucha@pwr.edu.pl.
Artur
A
Mucha
D000818:Animals; D001665:Binding Sites; D018826:CD13 Antigens / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry; D006801:Humans; D007931:Leucyl Aminopeptidase; D008024:Ligands; D010721:Phosphinic Acids / Q000737:chemistry; D010757:Phosphorous Acids; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine
D004151:Dipeptides; D008024:Ligands; D010721:Phosphinic Acids; D010757:Phosphorous Acids; D011480:Protease Inhibitors; D007931:Leucyl Aminopeptidase; D018826:CD13 Antigens
APN-inhibitor complex structures; Aminopeptidase N; Metalloaminopeptidases; Neisseria meningitidis; Phosphonic and phosphinic acids; S1 binding mode