Specificity of Memapsin 1 and Its Implications on the Design of Memapsin 2 (β-Secretase) Inhibitor Selectivity

• Published in: Biochemistry (Easton) Vol. 41; no. 27; pp. 8742 - 8746
• Main Authors: Turner, Robert T, Loy, Jeffrey A, Nguyen, Chan, Devasamudram, Thippeswamy, Ghosh, Arun K, Koelsch, Gerald, Tang, Jordan
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 09-07-2002
• Subjects: Amino Acid Sequence; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Catalytic Domain; Endopeptidases; Glycoproteins - chemistry; Glycoproteins - metabolism; Humans; Kinetics; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptide Library; Protease Inhibitors - pharmacology; Substrate Specificity
• DOI: 10.1021/bi025926t
• EISSN: 1520-4995
• ISSN: 0006-2960

Memapsin 1 is closely homologous to memapsin 2 (BACE), or β-secretase, whose action on β-amyloid precursor protein (APP) leads to the production of β-amyloid (Aβ) peptide and the progression of Alzheimer's disease. Memapsin 2 is a current target for the development of inhibitor drugs to treat Alzheimer's disease. Although memapsin 1 hydrolyzes the β-secretase site of APP, it is not significantly present in the brain, and no direct evidence links it to Alzheimer's disease. We report here the residue specificity of eight memapsin 1 subsites. In substrate positions P4, P3, P2, P1, P1‘, P2‘, P3‘, and P4‘, the most preferred residues are Glu, Leu, Asn, Phe, Met, Ile, Phe, and Trp, respectively, while the second preferred residues are Gln, Ile, Asp, Leu, Leu, Val, Trp, and Phe, respectively. Other less preferred residues can also be accommodated in these subsites of memapsin 1. Despite the broad specificity, these residue preferences are strikingly similar to those of human memapsin 2 [Turner et al. (2001) Biochemistry 40, 10001−10006] and thus pose a serious problem to the design of differentially selective inhibitors capable of inhibiting memapsin 2. This difficulty was confirmed by the finding that several potent memapsin 2 inhibitors effectively inhibited memapsin 1 as well. Several possible approaches to overcome this problem are discussed.