Development of Novel Benzodiazepine‐Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense

Abstract

Starting from the reversible rhodesain inhibitors 1 a–c, which have Ki values towards the target protease in the low‐micromolar range, we have designed a series of peptidomimetics, 2 a–g, that contain a benzodiazepine scaffold as a β‐turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael‐acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversible rhodesain inhibitor (i. e., 2 g) with a k2nd value of 90 000 M−1 min−1 that showed antitrypanosomal activity in the low‐micromolar range (EC50=1.25 μM), this may be considered a promising lead compound in the drug‐discovery process for treating human African trypanosomiasis (HAT).

Structure-based lead optimization of peptide-based vinyl methyl ketones as SARS-CoV-2 main protease inhibitors

“…Recently, we reported the results of a virtual screening campaign against SARS-CoV-2 M pro using an our in-house library of peptidic and non-peptidic ligands characterized by different types of electrophilic warheads [ 26 ], initially developed as inhibitors of rhodesain, a cysteine protease of Trypanosoma brucei rhodesiense [ [27] , [28] , [29] , [30] , [31] , [32] , [33] ]. Starting from the N3-SARS-CoV-2 M pro complex (PDB: 7BQY ) [ 23 ], the 106 in-house compounds were docked into the binding site of SARS-CoV-2 M pro .…”

Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis

“…E-64 protease inhibitor [76] was employed as the positive control. All the assayed compounds showed a high percentage of inhibition at the screening concentration (>80% at 100 µM), and for this reason SPR10-SPR19 and SPR34 were appropriately diluted and K i , k inact , and k 2nd values were determined [49,54]. Each independent assay was performed twice and in duplicate, using 96 well-plates in a total volume of 200 µM.…”

“…However, the presence of the secondary amine affects the vinyl ketone warhead of our most potent inhibitors: in fact, the R 2 -NH group could easily react with aldehydes and ketones providing carbinolamines, which spontaneously dehydrate to give enamines. In light of this, we decided to replace the methyl vinyl ketone warhead with the methyl ester analog, which is stable in the presence of secondary amines and proven to be a valid electron-withdrawing group (EWG) to activate the vinyl portion [49,54]. The Phe and hPhe residues at the P2 and P1 sites, respectively, were kept unchanged due to their fitting well into the corresponding enzyme pockets.…”

The Anti-Amoebic Activity of a Peptidomimetic against Acanthamoeba castellanii

“…Novel pyridine-cysteine containing cyclic peptidomimetics have shown high activity against Candida albicans and Gram-negative bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Proteus vulgaris [32]. Benzodiazepine-based peptidomimetics had activity against the protozoa, Trypanosoma brucei brucei, which causes sleeping sickness in humans [33]. The current authors have developed various peptidomimetics which are active against antibiotic-resistant bacteria such as Staphylococcus aureus, Escherichia coli [34], and Pseudomonas aeruginosa [35].…”