Gunther Bal

Natural substrates of dipeptidyl peptidase IV

During the last decade it has become clear that DPP IV may have various substrates in vivo and that the preferred peptide will depend on the localization and physiological circumstances. It is at present impossible to depict a certain chain length as the maximal acceptable substrate size as it turns out that the immediate surrounding and surface accessibility of the NH2-terminal dipeptide are determining the susceptibility for cleavage of a peptide.

Prolylisoxazoles: potent inhibitors of prolyloligopeptidase with antitrypanosomal activity

Prolylprolylisoxazoles and prolylprolylisoxazolines were synthesized through a 1,3-dipolar cycloaddition reaction. These compounds are potent inhibitors of human and trypanosomal prolyloligopeptidase. They were shown to inhibit Trypanosoma cruzi and Trypanosoma b. brucei in in vitro systems with ED(50)s in the lower microM range.

Development of potent and selective dipeptidyl peptidase II inhibitors.

Structure-activity investigations of product-like dipeptide analogues lacking the C-terminal carbonyl function resulted in potent and selective dipeptidyl peptidase II (DPP II) inhibitors. Dab-Pip has an IC(50)=0.13 microM for DPP II and a 7600-fold selectivity with respect to DPP IV. This compound will be highly valuable for the investigation of the biochemical function of DPP II.

N-Arylmethyl substituted iminoribitol derivatives as inhibitors of a purine specific nucleoside hydrolase.

A key enzyme within the purine salvage pathway of parasites, nucleoside hydrolase, is proposed as a good target for new antiparasitic drugs. We have developed N-arylmethyl-iminoribitol derivatives as a novel class of inhibitors against a purine specific nucleoside hydrolase from Trypanosoma vivax. Several of our inhibitors exhibited low nanomolar activity, with 1,4-dideoxy-1,4-imino-N-(8-quinolinyl)methyl-d-ribitol (UAMC-00115, K(i) 10.8nM), N-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.1nM), and N-(9-deazahypoxanthin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.4nM) being the three most active compounds. Docking studies of the most active inhibitors revealed several important interactions with the enzyme. Among these interactions are aromatic stacking of the nucleobase mimic with two Trp-residues, and hydrogen bonds between the hydroxyl groups of the inhibitors and amino acid residues in the active site. During the course of these docking studies we also identified a strong interaction between the Asp40 residue from the enzyme and the inhibitor. This is an interaction which has not previously been considered as being important.

Glutathione-like tripeptides as inhibitors of glutathionylspermidine synthetase. Part 1: Substitution of the glycine carboxylic acid group.

Glutathionylspermidine synthetase/amidase (GspS) is an essential enzyme in the biosynthesis and turnover of trypanothione and represents an attractive target for the design of selective anti-parasitic drugs. We synthesised a series of analogues of glutathione (L-gamma-Glu-L-Leu-Gly-X) where the glycine carboxylic acid group (X) has been substituted for other acidic groups such as tetrazole, hydroxamic acid, acylsulphonamide and boronic acid. The boronic acid appears the most promising lead compound (IC(50) of 17.2 microM).

Glutathione-like tripeptides as inhibitors of glutathionylspermidine synthetase. Part 2: substitution of the glycine part.

Glutathionylspermidine synthetase (GspS) is an essential enzyme in the biosynthesis of trypanothione and is an attractive target for the design of selective anti-parasitic drugs. We synthesised a series of analogues of glutathione (L-gamma-Glu-L-Leu-X) where the glycine moiety has been substituted for other amino acids. These peptides were evaluated as substrates and inhibitors of GspS. Compounds with basic side chains such as diaminopropionic acid were found to be good inhibitors (K(i): 7.2 microM). Substitution of the glycine part abolished the GspS substrate properties of the tripeptide.

Synthesis of Bicyclic N-Arylmethyl-Substituted Iminoribitol Derivatives as Selective Nucleoside Hydrolase Inhibitors

A series of bicyclic N‐arylmethyl‐substituted iminoribitols were synthesised and evaluated in vitro against T. vivax nucleoside hydrolase. The importance of the N–Asp40 interaction was confirmed and depends on an optimal pKa value, which can be influenced by substituents. The compounds were active inhibitors of nucleoside hydrolase (IAG‐NH) and are inactive against human purine nucleoside phosphorylase.

Polymer-assisted solution-phase parallel synthesis of dipeptide **p**-nitroanilides and dipeptide diphenyl phosphonates

Abstract This letter describes the parallel synthesis of dipeptide p-nitroanilides ( 1 ) and dipeptide diphenyl phosphonates ( 2 ), compounds that can be used as substrates and irreversible inhibitors for the rapid profiling of dipeptidyl peptidases. A polymer-assisted solution-phase synthesis was used for a rapid and clean coupling between easily available building blocks.