191033-19-9Relevant academic research and scientific papers
Leveraging the cruzain S3 subsite to increase affinity for reversible covalent inhibitors
Cianni, Lorenzo,Sartori, Geraldo,Rosini, Fabiana,De Vita, Daniela,Pires, Gabriel,Lopes, Bianca Rebelo,Leit?o, Andrei,Burtoloso, Antonio C.B.,Montanari, Carlos A.
, p. 285 - 292 (2018)
Cruzain is the major cysteine protease of Trypanosoma cruzi, the etiological agent of Chagas disease. Reversible covalent cruzain inhibitors can block the steps of cell differentiation in the parasite and kill the organism. To this end, the description of
N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design, synthesis and biochemical characterization
Lemke, Carina,Cianni, Lorenzo,Feldmann, Christian,Gilberg, Erik,Yin, Jiafei,dos Reis Rocho, Fernanda,de Vita, Daniela,Bartz, Ulrike,Bajorath, Jürgen,Montanari, Carlos A.,Gütschow, Michael
, (2020)
A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a t
Mapping the s1 and s1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents
Cianni, Lorenzo,Lemke, Carina,Gilberg, Erik,Feldmann, Christian,Rosini, Fabiana,Rocho, Fernanda Dos Reis,Ribeiro, Jean F. R.,Tezuka, Daiane Y.,Lopes, Carla D.,de Albuquerque, Sérgio,Bajorath, Jürgen,Laufer, Stefan,Leit?o, Andrei,Gütschow, Michael,Montanariid, Carlos A.
, (2020/04/24)
The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1′ subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a Ki smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC50 value of ca. 4.0 μM, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases.
2H-1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design
Giroud, Maude,Kuhn, Bernd,Saint-Auret, Sarah,Kuratli, Christoph,Martin, Rainer E.,Schuler, Franz,Diederich, Fran?ois,Kaiser, Marcel,Brun, Reto,Schirmeister, Tanja,Haap, Wolfgang
supporting information, p. 3370 - 3388 (2018/05/01)
Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold. In the S2 pocket, 3,4-dichlorophenylalanine residues provided high trypanocidal activities. In the S3 pocket, aromatic residues provided enhanced selectivity against hCatL. RD inhibition (Ki values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC50 values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1H-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability in human liver microsomes and in vivo half-lives of up to 1.53 h in mice. When orally administered to infected mice, parasitaemia was reduced but without complete removal of the parasites.
Experimental study and computational modelling of cruzain cysteine protease inhibition by dipeptidyl nitriles
Dos Santos, Alberto Monteiro,Cianni, Lorenzo,De Vita, Daniela,Rosini, Fabiana,Leit?o, Andrei,Laughton, Charles A.,Lameira, Jer?nimo,Montanari, Carlos A.
, p. 24317 - 24328 (2018/10/05)
Chagas disease affects millions of people in Latin America. This disease is caused by the protozoan parasite Trypanossoma cruzi. The cysteine protease cruzain is a key enzyme for the survival and propagation of this parasite lifecycle. Nitrile-based inhib
Direct dialkylation of peptide nitriles. Application to the synthesis of 1-aminocyclopropane-1-carboxylic acid (Acc)-containing dipeptides
McMath, Andrew R.,Guillaume, Dominique,Aitken, David J.,Husson, Henri-Philippe
, p. 105 - 110 (2007/10/03)
Several 1-aminocyclopropane-1-carboxylic acid-containing dipeptides (Acc-CP) have been prepared by regioselective dialkylation of peptoids containing α-aminonitriles as C-terminal residues.Regioselective deprotonation of the aminomethylene center using a
