Progress in the Development of Aminopeptidase N (APN/CD13) Inhibitors

Abstract

Aminopeptidase N (APN; CD13) is a member of zinc-containing ectoenzymes family involved in the degradation of neutral or basic amino acids (Ala>Phe>Leu>Gly) from N-terminal of bioactive peptides and amide or arylamide derivatives of amino acids. The expression of APN being up regulated has been implicated in the pathogenesis of a variety of diseases such as cancer, leukemia, diabetic nephropathy, and rheumatoid arthritis. Thus, APN inhibitors (APNIs) are expected to be useful for the treatment of these disorders. This article reviews briefly the structure characteristic and possible function of APN. The proposed biomolecular structures and mechanism of action used in the design of APNIs are thoroughly covered. Major emphasis is on recently published potent, small molecular weight APNIs and their essential structure activity relationship (SAR). Finally, available clinical results of compounds in development are summarized in this review.

LYP, a novel bestatin derivative, inhibits cell growth and suppresses APN/CD13 activity in human ovarian carcinoma cells more potently than bestatin

“…LYP design was based upon the 3-dimensional structure of APN/CD13 in which there are three hydrophobic pockets, S1, S1′ and S2′ [13]. Computer-based analysis showed that the benzene ring and isobutyl moiety of bestatin interacted well with the S1 and S1′ pockets but lacked a good interaction with the S2′ pocket [28][29][30]. In contrast, the DMAE moiety in LYP binds and interacts well with the S2′ pocket forming a hydrogen bond between the nitrogen atom of the tertiary amine moiety and the Arg825 [13].…”

A bestatin-based fluorescent probe for aminopeptidase N cell imaging

“…However, the recognition moiety (inhibitor) used in Cy 5.5-23 was not a potent APN ligand, which may lead to unpredicted and unspecific issue. So far, various inhibitors have been well developed toward APN, and one case in point is Bestatin, which is a dipeptide immunomodulator isolated from a culture filtrate of Streptomyces olivoreticuli with a skeleton of AHPA [25,26]. As the sole marketed APN inhibitor, Bestatin's pharmacokinetics and biotransformation has been examined in detail.…”

Peptidomimetics and metalloprotease inhibitors as anticancer drugs

“…; and synthetic compounds including α-aminophosphates (RB129, Figure 17) [24] , α -aminoaldehydes, β-aminothiols (e.g. α-Thiobestatin) [25] , α-ketoamides, α-amino boric acids, AHPA derivatives, L-isoglutamines, cyclo-imides, β-thiophenols and hydroxamates [26] , etc.…”