TY  - JOUR
A1  - Previti, Santo
A1  - Ettari, Roberta
A1  - Di Chio, Carla
A1  - Ravichandran, Rahul
A1  - Bogacz, Marta
A1  - Hellmich, Ute
A1  - Schirmeister, Tanja
A1  - Cosconati, Sandro
A1  - Zappalà, Maria
T1  - Development of reduced peptide bond pseudopeptide Michael acceptors for the treatment of Human African Trypanosomiasis
T2  - Molecules
N2  - Human African Trypanosomiasis (HAT) is an endemic protozoan disease widespread in the sub-Saharan region that is caused by T. b. gambiense and T. b. rhodesiense. The development of molecules targeting rhodesain, the main cysteine protease of T. b. rhodesiense, has led to a panel of inhibitors endowed with micro/sub-micromolar activity towards the protozoa. However, whilst impressive binding affinity against rhodesain has been observed, the limited selectivity towards the target still remains a hard challenge for the development of antitrypanosomal agents. In this paper, we report the synthesis, biological evaluation, as well as docking studies of a series of reduced peptide bond pseudopeptide Michael acceptors (SPR10–SPR19) as potential anti-HAT agents. The new molecules show Ki values in the low-micro/sub-micromolar range against rhodesain, coupled with k2nd values between 1314 and 6950 M−1 min−1. With a few exceptions, an appreciable selectivity over human cathepsin L was observed. In in vitro assays against T. b. brucei cultures, SPR16 and SPR18 exhibited single-digit micromolar activity against the protozoa, comparable to those reported for very potent rhodesain inhibitors, while no significant cytotoxicity up to 70 µM towards mammalian cells was observed. The discrepancy between rhodesain inhibition and the antitrypanosomal effect could suggest additional mechanisms of action. The biological characterization of peptide inhibitor SPR34 highlights the essential role played by the reduced bond for the antitrypanosomal effect. Overall, this series of molecules could represent the starting point for further investigations of reduced peptide bond-containing analogs as potential anti-HAT agents
KW  - sleeping sickness
KW  - Michael acceptors
KW  - peptide backbone modifications
KW  - antitrypanosomal agents
KW  - rhodesain
KW  - pseudopeptides
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/72090
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-720901
SN  - 1420-3049
N1  - Part of this work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy-EXC 2051*Project-ID 390713860.
N1  - Samples of the compounds SPR10–SPR19 and SPR34 are available from the authors.
VL  - 27
IS  - 12, art. 3765
SP  - 1
EP  - 21
PB  - MDPI
CY  - Basel
ER  -