Structure−Activity Relationships of Boronic Acid Inhibitors of Dipeptidyl Peptidase IV. 1. Variation of the P₂Position of X_aa-boroPro Dipeptides

Abstract

A series of prolineboronic acid (boroPro) containing dipeptides were synthesized and assayed for their ability to inhibit the serine protease dipeptidyl peptidase IV (DPPIV). Inhibitory activity, which requires the (R)-stereoisomer of boroPro in the P1 position, appears to tolerate a variety of L-amino acids in the P2 position. Substitution at the P2 position which is not tolerated include the D-amino acids, alpha,alpha-disubstituted amino acids, and glycine. Specificity against DPPII and proline specific endopeptidase is reported. A correlation between the ability to inhibit DPPIV in cell culture and in the human mixed lymphocyte reaction is demonstrated. A synthesis of prolineboronic acid is reported as well as conditions for generating the fully unprotected boronic acid dipeptides in either their cyclic or acyclic forms.

Cleavage Specificity of Mycobacterium tuberculosis ClpP1P2 Protease and Identification of Novel Peptide Substrates and Boronate Inhibitors with Anti-bacterial Activity

“…Except for N-(picolinoyl)-Lys-boroMet and N-(benzo[b]-thiophene-7-carbonyl)-Lys-boroMet (see below), all compounds were well characterized and reported (22). The target compounds were purified by reverse-phase (RP)-HPLC using a Varian semi-preparative system with a Discovery C18 569226-U RP-HPLC column.…”

Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies

“…Although PT-100 was originally designed as a competitive inhibitor of CD26/DPP-IV with high affinity for the catalytic site, 19 it also interacts with FAP because these molecules share a high degree of homology in this region. 14,28 Consequently, cultured human BM stromal cells, which as described above were responsive to PT-100, were analyzed for the presence of CD26/DPP-IV and FAP.…”

“…12 The potential regulatory role of selective proteolysis in hematopoiesis was suggested by one report in which a synthetic amino boronic dipeptide that specifically inhibited CD26/DPP-IV enzymatic activity appeared to have stimulatory activity in in vitro assays of rat progenitor cell proliferation. 18 As a class of compounds, amino boronic dipeptides are particularly attractive as experimental probes and potential therapeutics because they are high-affinity transition state analogs for the catalytic site of several serine proteses 19 and are readily bioavailable in vivo. 20 We have investigated the hematopoietic activity of the amino boronic dipeptide, Val-boro-Pro (PT-100).…”

PT-100, a Small Molecule Dipeptidyl Peptidase Inhibitor, Has Potent Antitumor Effects and Augments Antibody-Mediated Cytotoxicity via a Novel Immune Mechanism

“…1), appeared to be an interesting drug candidate in this context. PT-100 competitively inhibits the dipeptidyl peptidase (DPP) activity of FAP and CD26/DPP-IV, and there is a high-affinity interaction with the catalytic site due to the formation of a complex between Ser 630/624 and the boron of PT-100 (11,19). The potential of PT-100 as an antitumor agent was intriguing in the light of our earlier observation that PT-100, apparently through its interaction with FAP, could stimulate hematopoiesis via the increased production of cytokines [including granulocyte colony-stimulating factor (G-CSF)] both in vitro in stromal cell supported human bone marrow cultures and in vivo in mice (11).…”